Heterocyclic amides as kinase inhibitors

ABSTRACT

Disclosed are compounds having the formula: 
     
       
         
         
             
             
         
       
         
         
           
             wherein X, Y, Z 1 , Z 2 , Z 3 , Z 4 , R 5 , R A , m, A. L, and B are as defined herein, and methods of making and using the same.

FIELD OF THE INVENTION

The present invention relates to heterocyclic amides that inhibit RIP1kinase and methods of making and using the same.

BACKGROUND OF THE INVENTION

Receptor-interacting protein-1 (RIP1) kinase, originally referred to asRIP, is a TKL family serine/threonine protein kinase involved in innateimmune signaling. RIP1 kinase is a RHIM domain containing protein, withan N-terminal kinase domain and a C-terminal death domain ((2005) TrendsBiochem. Sci. 30, 151-159). The death domain of RIP1 mediatesinteraction with other death domain containing proteins including Fasand TNFR-1 ((1995) Cell 81 513-523), TRAIL-R1 and TRAIL-R2 ((1997)Immunity 7, 821-830) and TRADD ((1996) Immunity 4, 387-396), while theRHIM domain is crucial for binding other RHIM domain containing proteinssuch as TRIF ((2004) Nat Immunol. 5, 503-507), DAI ((2009) EMBO Rep. 10,916-922) and RIP3 ((1999) J. Biol. Chem. 274, 16871-16875); (1999) Curr.Biol. 9, 539-542) and exerts many of its effects through theseinteractions. RIP1 is a central regulator of cell signaling and isinvolved in mediating both pro-survival and programmed cell deathpathways which will be discussed below.

The role for RIP1 in cell signaling has been assessed under variousconditions [including TLR3 ((2004) Nat Immunol. 5, 503-507), TLR4((2005) J. Biol. Chem. 280, 36560-36566), TRAIL ((2012) J. Virol. Epub,ahead of print), FAS ((2004) J. Biol. Chem. 279, 7925-7933)], but isbest understood in the context of mediating signals downstream of thedeath receptor TNFR1 ((2003) Cell 114, 181-190). Engagement of the TNFRby TNF leads to its oligomerization, and the recruitment of multipleproteins, including linear K63-linked polyubiquitinated RIP1 ((2006)Mol. Cell 22, 245-257), TRAF2/5 ((2010) J. Mol. Biol. 396, 528-539),TRADD ((2008) Nat. Immunol. 9, 1037-1046) and cIAPs ((2008) Proc. Natl.Acad. Sci. USA. 105, 11778-11783), to the cytoplasmic tail of thereceptor. This complex which is dependent on RIP1 as a scaffoldingprotein (i.e. kinase independent), termed complex I, provides a platformfor pro-survival signaling through the activation of the NFκB and MAPkinases pathways ((2010) Sci. Signal. 115, re4). Alternatively, bindingof TNF to its receptor under conditions promoting the deubiquitinationof RIP1 (by proteins such as A20 and CYLD or inhibition of the cIAPs)results in receptor internalization and the formation of complex II orDISC (death-inducing signaling complex) ((2011) Cell Death Dis. 2,e230). Formation of the DISC, which contains RIP1, TRADD, FADD andcaspase 8, results in the activation of caspase 8 and the onset ofprogrammed apoptotic cell death also in a RIP1 kinase independentfashion ((2012) FEBS J 278, 877-887). Apoptosis is largely a quiescentform of cell death and is involved in routine processes such asdevelopment and cellular homeostasis.

Under conditions where the DISC forms and RIP3 is expressed, butapoptosis is inhibited (such as FADD/caspase 8 deletion, caspaseinhibition or viral infection), a third RIP1 kinase-dependentpossibility exists. RIP3 can now enter this complex, becomephosphorylated by RIP1 and initiate a caspase-independent programmednecrotic cell death through the activation of MLKL and PGAM5 ((2012)Cell 148, 213-227); ((2012) Cell 148, 228-243); ((2012) Proc. Natl.Acad. Sci. USA. 109, 5322-5327). As opposed to apoptosis, programmednecrosis (not to be confused with passive necrosis which is notprogrammed) results in the release of danger associated molecularpatterns (DAMPs) from the cell. These DAMPs are capable of providing a“danger signal” to surrounding cells and tissues, elicitingproinflammatory responses including inflammasome activation, cytokineproduction and cellular recruitment ((2008 Nat. Rev. Immunol 8,279-289).

Dysregulation of RIP1 kinase-mediated programmed cell death has beenlinked to various inflammatory diseases, as demonstrated by use of theRIP3 knockout mouse (where RIP1-mediated programmed necrosis iscompletely blocked) and by Necrostatin-1 (a tool inhibitor of RIP1kinase activity with poor oral bioavailability). The RIP3 knockout mousehas been shown to be protective in inflammatory bowel disease (includingUlcerative colitis and Crohn's disease) ((2011) Nature 477, 330-334),Psoriasis ((2011) Immunity 35, 572-582), retinal-detachment-inducedphotoreceptor necrosis ((2010) PNAS 107, 21695-21700), retinitispigmentosa ((2012) Proc. Natl. Acad. Sci., 109:36, 14598-14603),cerulein-induced acute pancreatitis ((2009) Cell 137, 1100-1111) andSepsis/systemic inflammatory response syndrome (SIRS) ((2011) Immunity35, 908-918). Necrostatin-1 has been shown to be effective inalleviating ischemic brain injury ((2005) Nat. Chem. Biol. 1, 112-119),retinal ischemia/reperfusion injury ((2010) J. Neurosci. Res. 88,1569-1576), Huntington's disease ((2011) Cell Death Dis. 2 el 15), renalischemia reperfusion injury ((2012) Kidney Int. 81, 751-761), cisplatininduced kidney injury ((2012) Ren. Fail. 34, 373-377) and traumaticbrain injury ((2012) Neurochem. Res. 37, 1849-1858). Other diseases ordisorders regulated at least in part by RIP1-dependent apoptosis,necrosis or cytokine production include hematological and solid organmalignancies ((2013) Genes Dev. 27: 1640-1649), bacterial infections andviral infections ((2014) Cell Host & Microbe 15, 23-35) (including, butnot limited to, tuberculosis and influenza ((2013) Cell 153, 1-14)) andLysosomal storage diseases (particularly, Gaucher Disease, NatureMedicine Advance Online Publication, 19 Jan. 2014, doi:10.1038/nm.3449).

A potent, selective, small molecule inhibitor of RIP1 kinase activitywould block RIP1-dependent cellular necrosis and thereby provide atherapeutic benefit in diseases or events associated with DAMPs, celldeath, and/or inflammation.

SUMMARY OF THE INVENTION

The invention is directed to compounds according to Formula (I):

wherein:

X is O, S, SO, SO₂, NH, CO, CH₂, CF₂, CH(CH₃), CH(OH), or N(CH₃);

Y is CH₂ or CH₂CH₂;

Z¹ is N, CH or CR¹;

Z² is CH or CR²;

Z³ is N, CH or CR³;

Z⁴ is CH or CR⁴;

R¹ is fluoro or methyl;

one of R² and R³ is halogen, cyano, (C₁-C₆)alkyl, halo(C₁-C₄)alkyl,(C₁-C₆)alkoxy, halo(C₁-C₄)alkoxy, hydroxyl, B(OH)₂, —COOH,halo(C₁-C₄)alkylC(OH)₂—, (C₁-C₄)alkoxy(C₁-C₄)alkoxy, (C₁-C₄)alkylSO₂-,(C₁-C₄)alkylSO₂NHC(O)—, (C₁-C₄)alkylC(O)NH—,((C₁-C₄)alkyl)((C₁-C₄)alkyl)NC(O)—, (C₁-C₄)alkylOC(O)—,(C₁-C₄)alkylC(O)N(C₁-C₄)alkyl)-, (C₁-C₄)alkylNHC(O)—,(C₁-C₄)alkoxy(C₂-C₄)alkylNHC(O)—, (C₁-C₄)alkoxy(C₂-C₄)alkylC(O)NH—,(C₁-C₄)alkoxy(C₂-C₄)alkylNHC(O)NH—, (C₁-C₄)alkylSO₂(C₂-C₄)alkylNHC(O)—,(C₁-C₄)alkylNHC(O)NH—, (C₁-C₄)alkylOC(O)NH—,hydroxy(C₁-C₄)alkylOC(O)NH—, 5-6 membered heterocycloalkyl-C(O)—, 5-6membered heterocycloalkyl-(C₁-C₄)alkyl-NHC(O)—, 5-6 memberedheterocycloalkyl-(C₁-C₄)alkoxy-, 3-6 membered cycloalkyl, 5-6 memberedheteroaryl, or 5-6 membered heteroaryl-C(O)NH,

wherein said 3-6 membered cycloalkyl, 5-6 membered heterocycloalkyl and5-6 membered heteroaryl are optionally substituted by 1 or 2substituents each independently selected from the group consisting of(C₁-C₄)alkyl and —(C₁-C₄)alkyl-CN;

and the other of R² and R³ is halogen or (C₁-C₆)alkyl;

R⁴ is fluoro, chloro, or methyl;

R⁵ is H or methyl;

A is phenyl, 5-6 membered heteroaryl, or 5-6 membered heterocycloalkyl,wherein the carbonyl moiety and L are substituted 1,3 on ring A;

m is 0 or m is 1 and R^(A) is (C₁-C₄)alkyl; and

L is O, S, NH, N(CH₃), CH₂, CH₂CH₂, CH(CH₃), CHF, CF₂, CH₂O, CH₂N(CH₃),CH₂NH, or CH(OH);

B is an optionally substituted (C₃-C₆)cycloalkyl, phenyl, 5-6 memberedheteroaryl, or 5-6 membered heterocycloalkyl;

wherein said (C₃-C₆)cycloalkyl, phenyl, 5-6 membered heteroaryl, or 5-6membered heterocycloalkyl is unsubstituted or is substituted by one ortwo substituents each independently selected from halogen, (C₁-C₄)alkyl,halo(C₁-C₄)alkyl, (C₁-C₄)alkoxy, halo(C₁-C₄)alkoxy, nitro, and(C₁-C₄)alkylC(O)—;

or the moiety -L-B is (C₃-C₆)alkyl, (C₃-C₆)alkoxy, halo(C₃-C₆)alkoxy,(C₃-C₆)alkenyl, or (C₃-C₆)alkenyloxy;

or a salt, particularly a pharmaceutically acceptable salt, thereof.

The compounds according to Formula (I), or salts, particularlypharmaceutically acceptable salts, thereof, are inhibitors of RIP1kinase.

Accordingly, the present invention is also directed to a method ofinhibiting RIP1 kinase which method comprises contacting a cell with acompound according to Formula (I), or a salt, particularly apharmaceutically acceptable salt, thereof.

The invention is further directed to a method of treating a RIP1kinase-mediated disease or disorder which comprises administering atherapeutically effective amount of a compound according to Formula (I),or a salt, particularly a pharmaceutically acceptable salt thereof, to apatient (a human or other mammal, particularly, a human) in needthereof. Such RIP1 kinase-mediated diseases or disorders includeinflammatory bowel disease (including Crohn's disease and ulcerativecolitis), psoriasis, retinal detachment, retinitis pigmentosa, arthritis(including rheumatoid arthritis, spondyloarthritis, gout, and SoJIA),transplant rejection, ischemia reperfusion injury of solid organs,multiple sclerosis, and tumor necrosis factor receptor-associatedperiodic syndrome.

The present invention is further directed to a pharmaceuticalcomposition comprising a compound according to Formula (I), or a salt,particularly a pharmaceutically acceptable salt, thereof and apharmaceutically acceptable excipient. Particularly, this invention isdirected to a pharmaceutical composition for the treatment of a RIP1kinase-mediated disease or disorder, where the composition comprises acompound according to Formula (I), or a salt, particularly apharmaceutically acceptable salt, thereof and a pharmaceuticallyacceptable excipient.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1A shows the temperature loss over time in mice after oralpre-dosing with the compound of Example 12 or vehicle followed bysimultaneous i.v. administration of mouse TNF and zVAD.

FIG. 1B shows the temperature loss in mice 2.5 hours after oralpre-dosing with the compound of Example 12 or vehicle followed bysimultaneous i.v. administration of mouse TNF and zVAD.

FIG. 2A shows the temperature loss over time in mice after oralpre-dosing with the compound of Example 12 or vehicle followed by i.v.administration of mouse TNF.

FIG. 2B shows the temperature loss in mice 6 hours after oral pre-dosingwith the compound of Example 12 or vehicle followed by i.v.administration of mouse TNF.

FIG. 3A shows the cellular levels of ATP in mouse L929 fibrosarcomacells pre-treated with the compound of Example 77 followed by treatmentwith TNFα+QvD.

FIG. 3B shows the cellular levels of ATP in human monocytic leukemiaU937 fibrosarcoma cells pre-treated with the compound of Example 77followed by treatment with TNFα+QvD.

FIG. 4A shows the temperature loss over time in mice after oralpre-dosing with the compound of Example 161 or vehicle followed bysimultaneous i.v. administration of mouse TNF and zVAD.

FIG. 4B shows the temperature loss in mice 6 hours after oral pre-dosingwith the compound of Example 161 or vehicle followed by simultaneousi.v. administration of mouse TNF and zVAD.

FIG. 5A shows the temperature loss over time in mice after oralpre-dosing with the compound of Example 161 or vehicle followed by i.v.administration of mouse TNF.

FIG. 5B shows the temperature loss in mice 6 hours after oral pre-dosingwith the compound of Example 161 or vehicle followed by i.v.administration of mouse TNF.

FIG. 6A shows the cellular levels of ATP in mouse L929 fibrosarcomacells pre-treated with the compound of Example 161 followed by treatmentwith TNFα+QvD.

FIG. 6B shows an IC₅₀ curve of ATP in human monocytic leukemia U937fibrosarcoma cells pre-treated with the compound of Example 161 followedby treatment with TNFα+QvD. Data are normalized to 10 mM Nec-1 which wasset at 100% survival.

FIG. 7 is a powder x-ray diffraction (PXRD) pattern of a crystallineform of anhydrous(S)-5-benzyl-N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4H-1,2,4-triazole-3-carboxamide(free base).

DETAILED DESCRIPTION OF THE INVENTION

This invention is also directed to a compound of Formula (I) wherein:

X is O, S, SO, SO₂, NH, CO, CH₂, CF₂, CH(CH₃), CH(OH), or N(CH₃);

Y is CH₂ or CH₂CH₂;

Z¹ is N, CH or CR¹;

Z² is CH or CR²;

Z³ is N, CH or CR³;

Z⁴ is CH or CR⁴;

R¹ is fluoro or methyl;

one of R² and R³ is halogen, cyano, (C₁-C₆)alkyl, halo(C₁-C₄)alkyl,(C₁-C₆)alkoxy, hydroxyl, B(OH)₂, —COOH, halo(C₁-C₄)alkylC(OH)₂—,(C₁-C₄)alkoxy(C₁-C₄)alkoxy, (C₁-C₄)alkylSO₂-, (C₁-C₄)alkylSO₂NHC(O)—,(C₁-C₄)alkylC(O)NH—, ((C₁-C₄)alkyl)((C₁-C₄)alkyl)NC(O)—,(C₁-C₄)alkylOC(O)—, (C₁-C₄)alkylC(O)N(C₁-C₄)alkyl)-,(C₁-C₄)alkylNHC(O)—, (C₁-C₄)alkoxy(C₂-C₄)alkylNHC(O)—,(C₁-C₄)alkoxy(C₂-C₄)alkylC(O)NH—, (C₁-C₄)alkoxy(C₂-C₄)alkylNHC(O)NH—,(C₁-C₄)alkylSO₂(C₂-C₄)alkylNHC(O)—, (C₁-C₄)alkylNHC(O)NH—,(C₁-C₄)alkylOC(O)NH—, hydroxy(C₁-C₄)alkylOC(O)NH—, 5-6 memberedheterocycloalkyl-C(O)—, 5-6 memberedheterocycloalkyl-(C₁-C₄)alkyl-NHC(O)—, 5-6 memberedheterocycloalkyl-(C₁-C₄)alkoxy-, 5-6 membered heteroaryl, or 5-6membered heteroaryl-C(O)NH,

wherein said 5-6 membered heterocycloalkyl and 5-6 membered heteroarylare optionally substituted by 1 or 2 substituents each independentlyselected from the group consisting of (C₁-C₄)alkyl and —(C₁-C₄)alkyl-CN;

and the other of R² and R³ is halogen or (C₁-C₆)alkyl;

R⁴ is fluoro, chloro, or methyl;

R⁵ is H or methyl;

A is phenyl, 5-6 membered heteroaryl, or 5-6 membered heterocycloalkyl,wherein the carbonyl moiety and L are substituted 1,3 on ring A;

m is 0 or m is 1 and R^(A) is (C₁-C₄)alkyl; and

L is O, S, NH, N(CH₃), CH₂, CH₂CH₂, CH(CH₃), CHF, CF₂, CH₂O, CH₂N(CH₃),CH₂NH, or CH(OH);

B is an optionally substituted (C₃-C₆)cycloalkyl, phenyl, 5-6 memberedheteroaryl, or 5-6 membered heterocycloalkyl;

wherein said (C₃-C₆)cycloalkyl, phenyl, 5-6 membered heteroaryl, or 5-6membered heterocycloalkyl is unsubstituted or is substituted by one ortwo substituents each independently selected from halogen, (C₁-C₄)alkyl,halo(C₁-C₄)alkyl, (C₁-C₄)alkoxy, halo(C₁-C₄)alkoxy, nitro, and(C₁-C₄)alkylC(O)—;

or the moiety -L-B is (C₃-C₆)alkyl, (C₃-C₆)alkoxy, halo(C₃-C₆)alkoxy,(C₃-C₆)alkenyl, or (C₃-C₆)alkenyloxy;

or a salt, particularly a pharmaceutically acceptable salt, thereof.

The alternative definitions for the various groups and substituentgroups of Formula (I) provided throughout the specification are intendedto particularly describe each compound species disclosed herein,individually, as well as groups of one or more compound species. Thescope of this invention includes any combination of these group andsubstituent group definitions. The compounds of the invention are onlythose which are contemplated to be “chemically stable” as will beappreciated by those skilled in the art.

As used herein, the term “alkyl” represents a saturated, straight orbranched hydrocarbon group having the specified number of carbon atoms.The term “(C₁-C₄)alkyl” refers to an alkyl moiety containing from 1 to 4carbon atoms. Exemplary alkyls include, but are not limited to methyl,ethyl, n-propyl, isopropyl, n-butyl, isobutyl, s-butyl, and t-butyl.

When a substituent term such as “alkyl” is used in combination withanother substituent term, for example as in “hydroxy(C₁-C₄)alkyl” or“aryl(C₁-C₄)alkyl”, the linking substituent term (e.g., alkyl) isintended to encompass a divalent moiety, wherein the point of attachmentis through that linking substituent. Examples of “aryl(C₁-C₄)alkyl”groups include, but are not limited to, benzyl (phenylmethyl),1-methylbenzyl (1-phenylethyl), and phenethyl (2-phenylethyl). Examplesof “hydroxy(C₁-C₄)alkyl” groups include, but are not limited to,hydroxymethyl, hydroxyethyl, and hydroxyisopropyl.

The term “halo(C₁-C₄)alkyl” represents a group having one or morehalogen atoms, which may be the same or different, at one or more carbonatoms of an alkyl moiety containing from 1 to 4 carbon atoms. Examplesof “halo(C₁-C₄)alkyl” groups include, but are not limited to, —CF₃(trifluoromethyl), —CCl₃ (trichloromethyl), 1,1-difluoroethyl,2,2,2-trifluoroethyl, and hexafluoroisopropyl.

“Alkenyl” refers to straight or branched hydrocarbon group having atleast 1 and up to 3 carbon-carbon double bonds. Examples include ethenyland propenyl.

“Alkoxy” refers to an “alkyl-oxy-” group, containing an alkyl moietyattached through an oxygen linking atom. For example, the term“(C₁-C₄)alkoxy” represents a saturated, straight or branched hydrocarbonmoiety having at least 1 and up to 4 carbon atoms attached through anoxygen linking atom. Exemplary “(C₁-C₄)alkoxy” groups include, but arenot limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy,s-butoxy, and t-butoxy.

The term “halo(C₁-C₄)alkoxy” refers to a “haloalkyl-oxy-” group,containing a “halo(C₁-C₄)alkyl” moiety attached through an oxygenlinking atom, which halo(C₁-C₄)alkyl” refers to a moiety having one ormore halogen atoms, which may be the same or different, at one or morecarbon atoms of an alkyl moiety containing from 1 to 4 carbon atoms.Exemplary “halo(C₁-C₄)alkoxy” groups include, but are not limited to,—OCHF₂ (difluoromethoxy), —OCF₃ (trifluoromethoxy), —OCH₂CF₃(trifluoroethoxy), and —OCH(CF₃)₂ (hexafluoroisopropoxy).

A carbocyclic group is a cyclic group in which all of the ring membersare carbon atoms, which may be saturated, partially unsaturated(non-aromatic) or fully unsaturated (aromatic). The term “carbocyclic”includes cycloalkyl and aryl groups.

“Cycloalkyl” refers to a non-aromatic, saturated, cyclic hydrocarbongroup containing the specified number of carbon atoms. For example, theterm “(C₃-C₆)cycloalkyl” refers to a non-aromatic cyclic hydrocarbonring having from three to six ring carbon atoms. Exemplary“(C₃-C₆)cycloalkyl” groups include cyclopropyl, cyclobutyl, cyclopentyl,and cyclohexyl.

The terms “cycloalkyloxy” or “cycloalkoxy” refer to a group containing acycloalkyl moiety, defined hereinabove, attached through an oxygenlinking atom. Exemplary “(C₃-C₆)cycloalkyloxy” groups includecyclopropyloxy, cyclobutyloxy, cyclopentyloxy, and cyclohexyloxy.

“Aryl” refers to a group or moiety comprising an aromatic, monocyclic orbicyclic hydrocarbon radical containing from 6 to 10 carbon ring atomsand having at least one aromatic ring. Examples of “aryl” groups arephenyl, naphthyl, indenyl, and dihydroindenyl (indanyl). Generally, inthe compounds of this invention, aryl is phenyl.

A heterocyclic group is a cyclic group having, as ring members, atoms ofat least two different elements, which cyclic group may be saturated,partially unsaturated (non-aromatic) or fully unsaturated (aromatic).The terms “heterocyclic” or “heterocyclyl” includes heterocycloalkyl andheteroaryl groups. It is to be understood that the terms heterocyclic,heterocyclyl, heteroaryl, and heterocycloalkyl, are intended toencompass stable groups where a ring nitrogen heteroatom is optionallyoxidized (e.g., heteroaryl groups containing an N-oxide, such asoxo-pyridyl (pyridyl-N-oxide) and oxo-oxadiazolyl(oxo-4,5-dihydro-1,3,4-oxadiazolyl) or where a ring sulfur heteroatom isoptionally oxidized (e.g., heterocycloalkyl groups containing sulfonesor sulfoxide moieties, such as tetrahydrothienyl-1-oxide(tetrahydrothienyl sulfoxide, tetrahydrothiophenyl sulfoxide) andtetrahydrothienyl-1,1-dioxide (tetrahydrothienyl sulfone)).

“Heterocycloalkyl” refers to a non-aromatic, monocyclic or bicyclicgroup containing 3-10 ring atoms, being saturated or having one or moredegrees of unsaturation and containing one or more (generally one ortwo) heteroatom substitutions independently selected from oxygen,sulfur, and nitrogen. Examples of “heterocycloalkyl” groups include, butare not limited to, aziridinyl, thiiranyl, oxiranyl, azetidinyl,oxetanyl, thietanyl, pyrrolidinyl, pyrrolinyl, pyrazolidinyl,pyrazolinyl, imidazolidinyl, imidazolinyl, oxazolinyl, thiazolinyl,tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, 1,3-dioxolanyl,piperidinyl, piperazinyl, tetrahydropyranyl, dihydropyranyl,tetrahydrothiopyranyl, 1,3-dioxanyl, 1,4-dioxanyl, 1,3-oxathiolanyl,1,3-oxathianyl, 1,3-dithianyl, 1,4-oxathiolanyl, 1,4-oxathianyl,1,4-dithianyl, morpholinyl, thiomorpholinyl,hexahydro-1H-1,4-diazepinyl, azabicylo[3.2.1]octyl,azabicylo[3.3.1]nonyl, azabicylo[4.3.0]nonyl, oxabicylo[2.2.1]heptyl,1,1-dioxidotetrahydro-2H-thiopyranyl, and 1,5,9-triazacyclododecyl.

Examples of “4-membered heterocycloalkyl” groups include oxetanyl,thietanyl and azetidinyl.

The term “5-6-membered heterocycloalkyl” represents a non-aromatic,monocyclic group, which is saturated or partially unsaturated,containing 5 or 6 ring atoms, which includes one or two heteroatomsselected independently from oxygen, sulfur, and nitrogen. Illustrativeexamples of 5 to 6-membered heterocycloalkyl groups include, but are notlimited to pyrrolidinyl, piperidinyl, piperazinyl, tetrahydrofuranyl,tetrahydrothienyl, tetrahydropyranyl, tetrahydrothiopyranyl,morpholinyl, and thiomorpholinyl.

“Heteroaryl” represents a group or moiety comprising an aromaticmonocyclic or bicyclic radical, containing 5 to 10 ring atoms, including1 to 4 heteroatoms independently selected from nitrogen, oxygen andsulfur. This term also encompasses bicyclic heterocyclic-aryl groupscontaining either an aryl ring moiety fused to a heterocycloalkyl ringmoiety or a heteroaryl ring moiety fused to a cycloalkyl ring moiety.

Illustrative examples of heteroaryls include, but are not limited to,furanyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl,tetrazolyl, thiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl,isothiazolyl, pyridinyl (pyridyl), oxo-pyridyl (pyridyl-N-oxide),pyridazinyl, pyrazinyl, pyrimidinyl, triazinyl, benzofuranyl,isobenzofuryl, 2,3-dihydrobenzofuryl, 1,3-benzodioxolyl,dihydrobenzodioxinyl, benzothienyl, indolizinyl, indolyl, isoindolyl,dihydroindolyl, benzimidazolyl, dihydrobenzimidazolyl, benzoxazolyl,dihydrobenzoxazolyl, benzothiazolyl, benzoisothiazolyl,dihydrobenzoisothiazolyl, indazolyl, imidazopyridinyl,pyrazolopyridinyl, benzotriazolyl, triazolopyridinyl, purinyl,quinolinyl, tetrahydroquinolinyl, isoquinolinyl,tetrahydroisoquinolinyl, quinoxalinyl, cinnolinyl, phthalazinyl,quinazolinyl, 1,5-naphthyridinyl, 1,6-naphthyridinyl,1,7-naphthyridinyl, 1,8-naphthyridinyl, and pteridinyl.

As used herein, “5-6-membered heteroaryl” represents an aromaticmonocyclic group containing 5 or 6 ring atoms, including at least onecarbon atom and 1 to 4 heteroatoms independently selected from nitrogen,oxygen and sulfur. Selected 5-membered heteroaryl groups contain onenitrogen, oxygen, or sulfur ring heteroatom, and optionally contain 1,2, or 3 additional nitrogen ring atoms. Selected 6-membered heteroarylgroups contain 1, 2, or 3 nitrogen ring heteroatoms. Examples of5-membered heteroaryl groups include furyl (furanyl), thienyl, pyrrolyl,imidazolyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, isothiazolyl,thiadiazolyl, oxazolyl, isoxazolyl, oxadiazolyl and oxo-oxadiazolyl.Selected 6-membered heteroaryl groups include pyridinyl, oxo-pyridyl,pyrazinyl, pyrimidinyl, pyridazinyl and triazinyl.

Bicyclic heteroaryl groups include 6,5-fused heteroaryl (9-memberedheteroaryl) and 6,6-fused heteroaryl (10-membered heteroaryl) groups.Examples of 6,5-fused heteroaryl (9-membered heteroaryl) groups includebenzothienyl, benzofuranyl, indolyl, indolinyl, isoindolyl,isoindolinyl, indazolyl, indolizinyl, isobenzofuryl,2,3-dihydrobenzofuryl, benzoxazolyl, benzthiazolyl, benzimidazolyl,benzoxadiazolyl, benzthiadiazolyl, benzotriazolyl,1,3-benzoxathiol-2-on-yl (2-oxo-1,3-benzoxathiolyl), purinyl andimidazopyridinyl.

Examples of 6,6-fused heteroaryl (10-membered heteroaryl) groups includequinolyl, isoquinolyl, phthalazinyl, naphthridinyl (1,5-naphthyridinyl,1,6-naphthyridinyl, 1,7-naphthyridinyl, 1,8-naphthyridinyl),quinazolinyl, quinoxalinyl, 4H-quinolizinyl, tetrahydroquinolinyl,cinnolinyl, and pteridinyl.

Unless otherwise specified, all bicyclic ring systems may be attached atany suitable position on either ring.

The terms “halogen” and “halo” represent chloro, fluoro, bromo, or iodosubstituents. “Oxo” represents a double-bonded oxygen moiety; forexample, if attached directly to a carbon atom forms a carbonyl moiety(C═O). “Hydroxy” or “hydroxyl” is intended to mean the radical —OH. Asused herein, the term “cyano” refers to the group —CN.

As used herein, the term “optionally substituted” indicates that a group(such as an alkyl, cycloalkyl, alkoxy, heterocycloalkyl, aryl, orheteroaryl group) or ring or moiety (such as a carbocyclic orheterocyclic ring or moiety) may be unsubstituted, or the group, ring ormoiety may be substituted with one or more substituent(s) as defined. Inthe case where groups may be selected from a number of alternativegroups, the selected groups may be the same or different.

The term “independently” means that where more than one substituent isselected from a number of possible substituents, those substituents maybe the same or different.

The term “pharmaceutically acceptable” refers to those compounds,materials, compositions, and dosage forms which are, within the scope ofsound medical judgment, suitable for use in contact with the tissues ofhuman beings and animals without excessive toxicity, irritation, orother problem or complication, commensurate with a reasonablebenefit/risk ratio.

As used herein, the terms “compound(s) of the invention” or “compound(s)of this invention” mean a compound of Formula (I), particularly acompound of any one of Formulas (I-IV), as defined herein, in any form,i.e., any salt or non-salt form (e.g., as a free acid or base form, oras a salt, particularly a pharmaceutically acceptable salt thereof) andany physical form thereof (e.g., including non-solid forms (e.g., liquidor semi-solid forms), and solid forms (e.g., amorphous or crystallineforms, specific polymorphic forms, solvate forms, including hydrateforms (e.g., mono-, di- and hemi-hydrates)), and mixtures of variousforms.

Accordingly, included within the present invention are the compounds ofFormula (I), particularly, compounds of any one of Formulas (I-IV), asdefined herein, in any salt or non-salt form and any physical formthereof, and mixtures of various forms. While such are included withinthe present invention, it will be understood that the compounds ofFormula (I), particularly, compounds of any one of Formulas (I-IV), asdefined herein, in any salt or non-salt form, and in any physical formthereof, may have varying levels of activity, differentbioavailabilities and different handling properties for formulationpurposes.

In one embodiment of the compounds of this invention, X is O, S, SO,SO₂, NH, CO, CH₂, CF₂, CH(CH₃), N(CH₃), or CH(OH). In a specificembodiment, X is O, S, SO, SO₂, NH, CO, CH₂, or N(CH₃). In anotherembodiment, X is S, SO, SO₂, or CO. In yet another embodiment, X is CF₂,CH(CH₃), or CH(OH). In a further embodiment, X is O, CH₂, NH or N(CH₃).

In selected embodiments, X is O or CH₂.

In one embodiment of the compounds of this invention, Y is CH₂ orCH₂CH₂. In another embodiment, Y is CH₂CH₂. In selected embodiments, Yis CH₂.

In one embodiment of the compounds this invention, Z¹, Z², Z³, and Z⁴are each CH. In another embodiment, Z¹ is CR¹ and Z², Z³ and Z⁴ are eachCH.

In a further embodiment, Z¹, Z², and Z⁴ are each CH and Z³ is CR³. In afurther embodiment, Z¹, Z³, and Z⁴ are each CH and Z² is CR². In a stillfurther embodiment, Z¹, Z², and Z³ are each CH and Z⁴ is CR⁴. In anotherembodiment, Z¹ and Z² are CH, Z³ is CR³, and Z⁴ is CR⁴. In anotherembodiment, Z¹ and Z⁴ are CH, Z² is CR², and Z³ is CR³. In anotherembodiment, Z¹ and Z³ are CH, Z² is CR², and Z⁴ is CR⁴. In anotherembodiment, Z¹ is CH, Z² is CR², Z³ is CR³, and Z⁴ is CR⁴.

In yet another embodiment of the compounds of this invention Z¹ and Z³are both N, Z² is CH and Z⁴ is CH or CR⁴. In yet another embodiment ofthe compounds of this invention Z¹ and Z³ are both N, Z² is CH or CR²and Z⁴ is CH. In still other embodiments, Z¹ is N, Z² is CR² and Z³ andZ⁴ are CH. In yet other embodiments, Z³ is N, and Z², Z³ and Z⁴ are CH.

In one embodiment of the compounds of this invention, R¹ is fluoro. Inanother embodiment, R¹ is methyl.

In one embodiment, one of R² and R³ is halogen, cyano, (C₁-C₆)alkyl,halo(C₁-C₄)alkyl, (C₁-C₆)alkoxy, halo(C₁-C₄)alkoxy, hydroxyl, B(OH)₂,—COOH, halo(C₁-C₄)alkylC(OH)₂—, (C₁-C₄)alkoxy(C₁-C₄)alkoxy,(C₁-C₄)alkylSO₂-, (C₁-C₄)alkylSO₂NHC(O)—, (C₁-C₄)alkylC(O)NH—,((C₁-C₄)alkyl)((C₁-C₄)alkyl)NC(O)—, (C₁-C₄)alkylOC(O)—,(C₁-C₄)alkylC(O)N(C₁-C₄)alkyl)-, (C₁-C₄)alkylNHC(O)—,(C₁-C₄)alkoxy(C₂-C₄)alkylNHC(O)—, (C₁-C₄)alkoxy(C₂-C₄)alkylC(O)NH—,(C₁-C₄)alkoxy(C₂-C₄)alkylNHC(O)NH—, (C₁-C₄)alkylSO₂(C₂-C₄)alkylNHC(O)—,(C₁-C₄)alkylNHC(O)NH—, (C₁-C₄)alkylOC(O)NH—,hydroxy(C₁-C₄)alkylOC(O)NH—, 5-6 membered heterocycloalkyl-C(O)—, 5-6membered heterocycloalkyl-(C₁-C₄)alkyl-NHC(O)—, 5-6 memberedheterocycloalkyl-(C₁-C₄)alkoxy-, 3-6 membered cycloalkyl, 5-6 memberedheteroaryl, or 5-6 membered heteroaryl-C(O)NH, wherein said 3-6 memberedcycloalkyl, 5-6 membered heterocycloalkyl and 5-6 membered heteroarylare optionally substituted by 1 or 2 substituents each independentlyselected from the group consisting of (C₁-C₄)alkyl and —(C₁-C₄)alkyl-CN;and the other of R² and R³ is halogen, cyano or (C₁-C₆)alkyl.

In one embodiment of the compounds of this invention, one of R² and R³is halogen, cyano, (C₁-C₆)alkyl, halo(C₁-C₄)alkyl, (C₁-C₆)alkoxy,hydroxyl, B(OH)₂, —COOH, halo(C₁-C₄)alkylC(OH)₂—,(C₁-C₄)alkoxy(C₁-C₄)alkoxy, (C₁-C₄)alkylSO₂-, (C₁-C₄)alkylSO₂NHC(O)—,(C₁-C₄)alkylC(O)NH—, ((C₁-C₄)alkyl)((C₁-C₄)alkyl)NC(O)—,(C₁-C₄)alkylOC(O)—, (C₁-C₄)alkylC(O)N(C₁-C₄)alkyl)-,(C₁-C₄)alkylNHC(O)—, (C₁-C₄)alkoxy(C₂-C₄)alkylNHC(O)—,(C₁-C₄)alkoxy(C₂-C₄)alkylC(O)NH—, (C₁-C₄)alkoxy(C₂-C₄)alkylNHC(O)NH—,(C₁-C₄)alkylSO₂(C₂-C₄)alkylNHC(O)—, (C₁-C₄)alkylNHC(O)NH—,(C₁-C₄)alkylOC(O)NH—, hydroxy(C₁-C₄)alkylOC(O)NH—, 5-6 memberedheterocycloalkyl-C(O)—, 5-6 memberedheterocycloalkyl-(C₁-C₄)alkyl-NHC(O)—, 5-6 memberedheterocycloalkyl-(C₁-C₄)alkoxy-, 5-6 membered heteroaryl, or 5-6membered heteroaryl-C(O)NH, wherein said 5-6 membered heterocycloalkyland 5-6 membered heteroaryl are optionally substituted by 1 or 2substituents each independently selected from the group consisting of(C₁-C₄)alkyl and —(C₁-C₄)alkyl-CN;

and the other of R² and R³ is halogen or (C₁-C₆)alkyl.

In another embodiment, R² is halogen, cyano, (C₁-C₆)alkyl,(C₁-C₆)alkoxy, halo(C₁-C₄)alkoxy, hydroxyl, B(OH)₂, —COOH,halo(C₁-C₄)alkylC(OH)₂—, (C₁-C₄)alkoxy(C₁-C₄)alkoxy, 3-5 memberedcycloalkyl, or 5-6 membered heteroaryl, wherein said 3-5 memberedcycloalkyl or 5-6 membered heteroaryl is optionally substituted by a(C₁-C₃)alkyl substituent; and Z³ is CH or CR³ and R³ is cyano,(C₁-C₆)alkyl, or a 5-6 membered heteroaryl, optionally substituted by a(C₁-C₃)alkyl substituent. In another embodiment, R² is halogen, cyano,(C₁-C₆)alkyl, hydroxyl, B(OH)₂, —COOH, halo(C₁-C₄)alkylC(OH)₂—,(C₁-C₄)alkoxy(C₁-C₄)alkoxy, or 5-6 membered heteroaryl, wherein said 5-6membered heteroaryl is optionally substituted by a (C₁-C₃)alkylsubstituent; and Z³ is CH.

In another embodiment, R³ is halogen, (C₁-C₆)alkyl, halo(C₁-C₄)alkyl,(C₁-C₆)alkoxy, halo(C₁-C₆)alkoxy, B(OH)₂, —COOH, (C₁-C₄)alkylSO₂-,(C₁-C₄)alkylSO₂NHC(O)—, (C₁-C₄)alkylC(O)NH—,((C₁-C₄)alkyl)((C₁-C₄)alkyl)NC(O)—, (C₁-C₄)alkylOC(O)—,(C₁-C₄)alkylC(O)N(C₁-C₄)alkyl)-, (C₁-C₄)alkoxy(C₂-C₄)alkylNHC(O)NH—,(C₁-C₄)alkylSO₂(C₂-C₄)alkylNHC(O)—, (C₁-C₄)alkylNHC(O)NH—,(C₁-C₄)alkylOC(O)NH—, hydroxy(C₁-C₄)alkylOC(O)NH—, 5-6 memberedheterocycloalkyl-C(O)—, 5-6 memberedheterocycloalkyl-(C₁-C₄)alkyl-NHC(O)—, 5-6 memberedheterocycloalkyl-(C₁-C₄)alkoxy-, 5-6 membered heteroaryl, or 5-6membered heteroaryl-C(O)NH, herein said 5-6 membered heterocycloalkyland 5-6 membered heteroaryl are optionally substituted by (C₁-C₃)alkylor —(C₁-C₃)alkyl-CN; and Z² is CH.

In another embodiment, R³ is halogen, (C₁-C₆)alkyl, halo(C₁-C₄)alkyl,(C₁-C₆)alkoxy, B(OH)₂, —COOH, (C₁-C₄)alkylSO₂-, (C₁-C₄)alkylSO₂NHC(O)—,(C₁-C₄)alkylC(O)NH—, ((C₁-C₄)alkyl)((C₁-C₄)alkyl)NC(O)—,(C₁-C₄)alkylOC(O)—, (C₁-C₄)alkylC(O)N(C₁-C₄)alkyl)-,(C₁-C₄)alkoxy(C₂-C₄)alkylNHC(O)NH—, (C₁-C₄)alkylSO₂(C₂-C₄)alkylNHC(O)—,(C₁-C₄)alkylNHC(O)NH—, (C₁-C₄)alkylOC(O)NH—,hydroxy(C₁-C₄)alkylOC(O)NH—, 5-6 membered heterocycloalkyl-C(O)—, 5-6membered heterocycloalkyl-(C₁-C₄)alkyl-NHC(O)—, 5-6 memberedheterocycloalkyl-(C₁-C₄)alkoxy-, 5-6 membered heteroaryl, or 5-6membered heteroaryl-C(O)NH, herein said 5-6 membered heterocycloalkyland 5-6 membered heteroaryl are optionally substituted by (C₁-C₃)alkylor —(C₁-C₃)alkyl-CN; and Z² is CH.

In specific embodiments, R² is fluoro, chloro, bromo, —CN, —CH₃, —OCH₃,—OCHF₂, —OH, B(OH)₂, CF₃C(OH)₂—, CH₃OCH₂CH₂O—, cyclopropyl,5H-tetrazol-5-yl, pyrazol-3-yl, or 5-methyl-1,3,4-oxadiazol-2-yl.

In other specific embodiments, R² is fluoro, chloro, bromo, —CN, —CH₃,—OH, B(OH)₂, CF₃C(OH)₂—, CH₃OCH₂CH₂O—, 5H-tetrazol-5-yl, pyrazol-3-yl,or 5-methyl-1,3,4-oxadiazol-2-yl.

In another specific embodiment, R² is chloro, bromo, —CN, —CH₃, —OH,B(OH)₂, CF₃C(OH)₂—, CH₃OCH₂CH₂O—, 5H-tetrazol-5-yl, pyrazol-3-yl, or5-methyl-1,3,4-oxadiazol-2-yl.

In specific embodiments, R³ is fluoro, chloro, bromo, —CN, —OCH₃,—OCHF₂, B(OH)₂, —COOH, CH₃SO₂—, CH₃SO₂NHC(O)—, CH₃C(O)NH—, (CH₃)₂NC(O)—,CH₃OC(O)—, (CH₃)C(O)N(CH₃)—, HOCH₂CH₂C(O)NH—, CH₃OCH₂CH₂NHC(O)NH—,CH₃SO₂CH₂CH₂NHC(O)—, CH₃CH₂NHC(O)NH—, CH₃OC(O)NH—, morpholin-4-yl-CO—,pyrrolidin-1-yl-CH₂CH₂NHC(O)—, pyridin-2-yl, tetrahydrofuran-2-yl-CH₂O—,pyrrolidin-1-yl-CH₂CH₂O—, tetrazol-5-yl, 1-(2-cyanoethyl)-tetrazol-5-yl,pyrazol-1-yl, pyrazol-3-yl, pyrazol-4-yl, 1-methyl-pyrazol-3-yl,1-methyl-pyrrol-4-yl-C(O)NH—, 5-methyl-1,3,4-oxadiazol-2-yl, or5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl.

In other specific embodiments, R³ is fluoro, chloro, bromo, —OCH₃,B(OH)₂, —COOH, CH₃SO₂—, CH₃SO₂NHC(O)—, CH₃C(O)NH—, (CH₃)₂NC(O)—,CH₃OC(O)—, (CH₃)C(O)N(CH₃)—, HOCH₂CH₂C(O)NH—, CH₃OCH₂CH₂NHC(O)NH—,CH₃SO₂CH₂CH₂NHC(O)—, CH₃CH₂NHC(O)NH—, CH₃OC(O)NH—, morpholin-4-yl-CO—,pyrrolidin-1-yl-CH₂CH₂NHC(O)—, tetrahydrofuran-2-yl-CH₂O—,pyrrolidin-1-yl-CH₂CH₂O—, tetrazol-5-yl, 1-(2-cyanoethyl)-tetrazol-5-yl,pyrazol-1-yl, pyrazol-3-yl, 1-methyl-pyrazol-3-yl,1-methyl-pyrrol-4-yl-C(O)NH—, 5-methyl-1,3,4-oxadiazol-2-yl, or5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl.

In still other embodiments, R³ is fluoro, chloro, bromo, —OCH₃, B(OH)₂,—COOH, CH₃SO₂—, CH₃SO₂NHC(O)—, CH₃C(O)NH—, (CH₃)₂NC(O)—, CH₃OC(O)—,(CH₃)C(O)N(CH₃)—, HOCH₂CH₂C(O)NH—, CH₃OCH₂CH₂NHC(O)NH—,CH₃SO₂CH₂CH₂NHC(O)—, CH₃CH₂NHC(O)NH—, CH₃OC(O)NH—, morpholin-4-yl-CO—,pyrrolidin-1-yl-CH₂CH₂NHC(O)—, tetrahydrofuran-2-yl-CH₂O—,pyrrolidin-1-yl-CH₂CH₂O—, tetrazol-5-yl, 1-(2-cyanoethyl)-tetrazol-5-yl,pyrazol-1-yl, pyrazol-3-yl, 1-methyl-pyrazol-3-yl,1-methyl-pyrrol-4-yl-C(O)NH—, or 5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl.

In one embodiment of the compounds of this invention, R⁴ is fluoro,chloro, methyl, or trifluoromethyl. In another embodiment, R⁴ is fluoro.In yet another embodiment, R⁴ is methyl.

In one embodiment of the compounds of this invention, R⁵ is H. Inanother embodiment, R⁵ is methyl.

In one embodiment of the compounds of this invention, A is phenyl, 5-6membered heteroaryl, or 5-6 membered heterocycloalkyl, wherein thecarbonyl moiety and L are substituted 1,3 on ring A.

In another embodiment, A is a 5 membered heteroaryl containing oneoxygen or sulfur atom and optionally containing one or two nitrogenatoms; specifically A is furyl, thienyl, oxazolyl, isoxazolyl,thiazolyl, or oxadiazolyl (more specifically, 1, 2, 4-oxadiazolyl or 1,3, 4-oxadiazolyl). In another embodiment, A is a 5 membered heteroarylcontaining one nitrogen atom and optionally containing one, two or threeadditional nitrogen atoms, specifically; A is pyrrolyl, pyrazolyl,imidazolyl, triazolyl (more specifically, 1, 2, 3-triazolyl or 1, 2,4-triazolyl) or tetrazolyl. In selected embodiments, A is triazolyl. Inyet embodiment of this invention, A is a 5 or 6 memberedheterocycloalkyl specifically, A is piperidinyl or pyrrolidinyl. In afurther embodiment of this invention, A is a 6-membered aromatic groupselected from phenyl and pyridyl.

Another embodiment of this invention is directed to a compound accordingto Formula (II):

wherein:

A¹ is C,

A⁴ is C or N,

and A², A³, and A⁵ are each independently selected from CH, CR^(A), O,S, N, NH and NR^(A) to form a furyl, thienyl, oxazolyl, isoxazolyl,thiazolyl, oxadiazolyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl ortetrazolyl ring moiety,

wherein said ring moiety contains 0 or 1 of CR^(A) and NR^(A); and

wherein X, Z¹, Z², Z³, Z⁴, R⁵, L, and B are as defined herein,

or a salt, particularly a pharmaceutically acceptable salt, thereof.

In selected embodiments, A¹ is C, A⁴ is C or N, and A², A³, and A⁵ areeach independently selected from CH, O, N, and NH to form an oxazolyl,isoxazolyl, oxadiazolyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl ortetrazolyl ring moiety.

In other selected embodiments, A¹ and A⁴ are each C, and A², A³ and A⁵are each independently selected from N and NH to form a triazolyl ringmoiety.

Another embodiment of this invention, wherein A is piperidinyl orpyrrolidinyl, may be represented by Formula (III):

wherein s is 0 or 1, A¹⁰ is N and X, Z¹, Z², Z³, Z⁴, R⁵ R^(A), m, L, andB are as defined herein. In specific embodiments, m is 0 and A is anunsubstituted piperidinyl or pyrrolidinyl moiety.

In one embodiment of the compounds of this invention, m is 0. In anotherembodiment, m is 1 and R^(A) is (C₁-C₄)alkyl, specifically R^(A) is(C₁-C₂)alkyl. In selected embodiments, R^(A) is methyl.

A further embodiment of this invention, wherein A is phenyl, pyridinyl,or pyridinyl-N-oxide, may be represented by Formula (IV):

wherein:

A⁶, A⁷, A⁸, and A⁹ are each CH;

one of A⁶, A⁷, A⁸, and A⁹ is CR^(A) and the others of A⁶, A⁷, A⁸, and A⁹are CH;

one of A⁶, A⁷, A⁸, and A⁹ is N and the others of A⁶, A⁷, A⁸, and A⁹ areCH;

one of A⁶, A⁷, A⁸, and A⁹ is N—O and the other of A⁶, A⁷, A⁸, and A⁹ areCH;

and X, Z¹, Z², Z³, Z⁴, R⁵, L, and B are as defined herein.

In one embodiment of the compounds of this invention, L is O, S, NH,N(CH₃), CH₂, CH₂CH₂, CH(CH₃), CHF, CF₂, CH₂O, CH₂N(CH₃), CH₂NH, orCH(OH). In another embodiment, L is O, S, N(CH₃), CH₂, CH₂CH₂, CH(CH₃),CF₂, CH₂O, CH₂N(CH₃), or CH(OH). In another embodiment, L is CH₂O,CH₂CH₂, CH₂NH, or CH₂N(CH₃). In a further embodiment, L is N(CH₃),CH(CH₃), or CH(OH). In another further embodiment, L is —(R)CH(CH₃). Ina still further embodiment, L is O, CH₂, or NH. In one selectedembodiment, L is O. In another selected embodiment, L is CH₂.

In one embodiment of the compounds of this invention, B is an optionallysubstituted (C₃-C₆)cycloalkyl, phenyl, 5-6 membered heteroaryl, or 5-6membered heterocycloalkyl; wherein said (C₃-C₆)cycloalkyl, phenyl, 5-6membered heteroaryl, or 5-6 membered heterocycloalkyl is unsubstitutedor is substituted by one or two substituents each independently selectedfrom halogen, (C₁-C₄)alkyl, halo(C₁-C₄)alkyl, (C₁-C₄)alkoxy,halo(C₁-C₄)alkoxy, nitro, and (C₁-C₄)alkylC(O)—. In one embodiment ofthe compounds of this invention, B is an optionally substituted 5-6membered heteroaryl or 5-6 membered heterocycloalkyl. In one embodiment,B is an optionally substituted pyrazolyl, thienyl, pyridinyl (pyridyl),oxo-pyridyl, pyrimidinyl, isoxazolyl, morpholinyl, tetrahydropyranyl ortetrahydrofuranyl, wherein the pyrazolyl, thienyl, pyridinyl (pyridyl),oxo-pyridyl, pyrimidinyl, isoxazolyl, morpholinyl, tetrahydropyranyl ortetrahydrofuranyl is optionally substituted by one or two independentlyselected (C₁-C₄)alkyl substituents. In another embodiment, Bis anoptionally substituted pyrazolyl, thienyl, pyridinyl (pyridyl),oxo-pyridyl, pyrimidinyl, isoxazolyl, morpholinyl, or tetrahydrofuranyl,wherein the pyrazolyl, thienyl, pyridinyl (pyridyl), oxo-pyridyl,pyrimidinyl, isoxazolyl, morpholinyl, or tetrahydrofuranyl is optionallysubstituted by one or two independently selected (C₁-C₄)alkylsubstituents. In specific embodiments, B is thien-2-yl (thiophen-2-yl),5-methyl-thien-2-yl (5-methyl-thiophen-2-yl), pyrazol-1-yl,3,5-dimethylpyrazol-1-yl, 4-methylpyrazol-1-yl,3,5-dimethylisoxazol-4-yl, tetrahydropyran-3-yl, tetrahydrofuran-2-yl,morpholin-4-yl, pyridin-2-yl, 2-oxo-pyridin-1-yl, 6-methylpyridin-3-yl,or 2-methylpyrimidin-5-yl.

In other specific embodiments, B is thien-2-yl (thiophen-2-yl),5-methyl-thien-2-yl (5-methyl-thiophen-2-yl), pyrazol-1-yl,3,5-dimethylpyrazol-1-yl, 4-methylpyrazol-1-yl,3,5-dimethylisoxazol-4-yl, tetrahydrofuran-2-yl, morpholin-4-yl,pyridin-2-yl, 2-oxo-pyridin-1-yl, 6-methylpyridin-3-yl, and2-methylpyrimidin-5-yl.

In specific embodiments, B is thien-2-yl, pyrazol-1-yl,3,5-dimethylpyrazol-1-yl, 4-methylpyrazol-1-yl,3,5-dimethylisoxazol-4-yl, tetrahydrofuran-2-yl, morpholin-4-yl,pyridin-2-yl, 2-oxo-pyridin-1-yl, 6-methylpyridin-3-yl, and2-methylpyrimidin-5-yl.

In another embodiment of the compounds of this invention, B isunsubstituted (C₃-C₆)cycloalkyl or phenyl. In a selected embodiment ofthis invention, B is unsubstituted cyclopropyl, cyclobutyl, cyclopentylor cyclohexyl. In a specific embodiment, B is unsubstituted cyclopentylor cyclohexyl. In another selected embodiment of the compounds of thisinvention, B is unsubstituted phenyl.

In another selected embodiment, B is substituted phenyl. In oneembodiment, B is phenyl, substituted by 1 or 2 substituentsindependently selected from halogen, (C₁-C₄)alkyl, halo(C₁-C₄)alkyl,(C₁-C₄)alkoxy, halo(C₁-C₄)alkoxy, nitro, and (C₁-C₄)alkylC(O)—. In otherembodiments, B is phenyl, substituted by 1 or 2 substituentsindependently selected from halogen, (C₁-C₃)alkyl and (C₁-C₃)alkoxy. Inspecific embodiments, B is phenyl, substituted by a substituent selectedfrom fluoro, chloro, bromo, iodo, nitro, methyl, ethyl, isopropyl,trifluoromethyl, methoxy, and —COCH₃. In specific embodiments, B isphenyl, substituted by 1 or 2 substituents independently selected fromiodo, fluoro, chloro, bromo, methyl and methoxy.

In one selected embodiment, B is phenyl, substituted by 1 or 2substituents independently selected from fluoro, chloro, bromo, andmethyl, specifically B is phenyl, substituted by 1 or 2 fluorosubstituents. In specific embodiments, B is cyclopentyl, cyclohexyl,2-methylphenyl, 4-methylphenyl, 2-trifluoromethylphenyl, 2-fluorophenyl,3-fluorophenyl, 4-fluorophenyl, 2-iodophenyl, 3-bromophenyl,4-bromophenyl, 4-chlorophenyl, 2,5-difluorophenyl, 2,4-difluorophenyl,3,4-difluorophenyl, 3,5-difluorophenyl, or 4-methoxyphenyl. In otherembodiments, B is 2,3-difluorophenyl or 2,6-difluorophenyl.

In one embodiment of the compounds of this invention, the moiety -L-B is(C₃-C₆)alkyl, (C₃-C₆)alkoxy, halo(C₃-C₆)alkoxy, (C₃-C₆)alkenyl, or(C₃-C₆)alkenyloxy. In another embodiment, the moiety -L-B is(C₃-C₆)alkyl, (C₃-C₆)alkoxy, or (C₃-C₅)alkenyloxy. In specificembodiments, -L-B is —OCH₂CH═CH₂, —CH₂CH₂CH₂CH₂CH₃, —OCH₂CH₂CH₂CH₃,—CH₂CH₂CH₃, —CH₂CH(CH₃)₂ or —CH₂CH₂CH(CH₃)₂. In other specificembodiments, -L-B is —OCH₂CH═CH₂, —CH₂CH₂CH₂CH₂CH₃, —OCH₂CH₂CH₂CH₃,—CH₂CH₂CH₃, or —CH₂CH(CH₃)₂.

Representative compounds of this invention include the compounds of theExamples. It will be appreciated that the present invention encompassescompounds of Formula (I) as the free base and as salts thereof, forexample as a pharmaceutically acceptable salt thereof. In one embodimentthe invention relates to compounds of Formula (I) in the form of a freebase. In another embodiment the invention relates to compounds ofFormula (I) in the form of a salt, particularly, a pharmaceuticallyacceptable salt. It will be further appreciated that, in one embodiment,the invention relates to compounds of the Examples in the form of a freebase. In another embodiment the invention relates to compounds of theExamples in the form of a salt, particularly, a pharmaceuticallyacceptable salt.

Specifically, this invention is directed to(S)-5-benzyl-N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4H-1,2,4-triazole-3-carboxamide;(S)-5-benzyl-N-(6-fluoro-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4H-1,2,4-triazole-3-carboxamide;and5-benzyl-N-(7-bromo-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-3-yl)-4H-1,2,4-triazole-3-carboxamide,or a salt thereof, particularly a pharmaceutically acceptable salt,thereof. Specifically, this invention is directed to(S)-5-benzyl-N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4H-1,2,4-triazole-3-carboxamide;(S)-5-benzyl-N-(6-fluoro-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4H-1,2,4-triazole-3-carboxamide;or5-benzyl-N-(7-bromo-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-3-yl)-4H-1,2,4-triazole-3-carboxamide,or a pharmaceutically acceptable salt, thereof.

More specifically, this invention is directed to(S)-5-benzyl-N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4H-1,2,4-triazole-3-carboxamideand(S)-5-benzyl-N-(7-chloro-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-3-yl)-4H-1,2,4-triazole-3-carboxamide,or a pharmaceutically acceptable salt thereof.

This invention is directed to(S)-5-benzyl-N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4H-1,2,4-triazole-3-carboxamideor a salt, particularly a pharmaceutically acceptable salt, thereof.Accordingly, one particular compound of the invention is(S)-5-benzyl-N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4H-1,2,4-triazole-3-carboxamide(free base). In another embodiment, the compound of the invention is asalt of(S)-5-benzyl-N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4H-1,2,4-triazole-3-carboxamide.In another embodiment, the compound of the invention is apharmaceutically acceptable salt of(S)-5-benzyl-N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4H-1,2,4-triazole-3-carboxamide.In another embodiment, the compound of the invention is a base-additionsalt of(S)-5-benzyl-N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4H-1,2,4-triazole-3-carboxamide.In still another embodiment, the compound of the invention is acrystalline form of anhydrous(S)-5-benzyl-N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4H-1,2,4-triazole-3-carboxamide(free base) characterized by the PXRD pattern of FIG. 7. In yet anotherembodiment, a particular compound of the invention is a crystalline formof anhydrous(S)-5-benzyl-N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4H-1,2,4-triazole-3-carboxamide(free base) characterized by the diffraction data in Table 1.

This invention is directed(S)-5-benzyl-N-(7-chloro-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-3-yl)-4H-1,2,4-triazole-3-carboxamide,or a salt, particularly a pharmaceutically acceptable salt, thereof.Accordingly, one particular compound of the invention is(S)-5-benzyl-N-(7-chloro-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-3-yl)-4H-1,2,4-triazole-3-carboxamide(free base). In another embodiment, the compound of the invention is asalt of(S)-5-benzyl-N-(7-chloro-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-3-yl)-4H-1,2,4-triazole-3-carboxamide.In another embodiment, the compound of the invention is apharmaceutically acceptable salt of(S)-5-benzyl-N-(7-chloro-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-3-yl)-4H-1,2,4-triazole-3-carboxamide.In another embodiment, the compound of the invention is a base-additionsalt of(S)-5-benzyl-N-(7-chloro-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-3-yl)-4H-1,2,4-triazole-3-carboxamide.

In a specific embodiment, this invention is directed to a compound ofFormula (I) wherein:

X is O, S, SO, SO₂, NH, CO, CH₂, or N(CH₃);

Y is CH₂ or CH₂CH₂;

Z¹, Z², Z³, and Z⁴ are each CH; or Z¹ is CR¹ and Z², Z³ and Z⁴ are eachCH; or Z¹, Z², and Z⁴ are each CH and Z³ is CR³; or Z¹, Z³, and Z⁴ areeach CH and Z² is CR²; or Z¹, Z², and Z³ are each CH and Z⁴ is CR⁴; orZ¹ and Z² are CH, Z³ is CR³, and Z⁴ is CR⁴; or Z¹ and Z⁴ are CH, Z² isCR², and Z³ is CR³; or Z¹ and Z³ are CH, Z² is CR², and Z⁴ is CR⁴; or Z¹is CH, Z² is CR², Z³ is CR³, and Z⁴ is CR⁴; or Z¹ and Z³ are both N, Z²is CH and Z⁴ is CH or CR⁴; or Z¹ and Z³ are both N, Z² is CH or CR² andZ⁴ is CH; or Z¹ is N, Z² is CR⁴ and Z³ and Z⁴ are CH; or Z³ is N, andZ², Z³ and Z⁴ are CH;

R¹ is methyl,

R² is fluoro, chloro, bromo, —CN, —CH₃, —OCH₃, —OCHF₂, —OH, B(OH)₂,CF₃C(OH)₂—, CH₃OCH₂CH₂O—, cyclopropyl, 5H-tetrazol-5-yl, pyrazol-3-yl,or 5-methyl-1,3,4-oxadiazol-2-yl;

R³ is fluoro, chloro, bromo, —CN, —OCH₃, —OCHF₂, B(OH)₂, —COOH, CH₃SO₂—,CH₃SO₂NHC(O)—, CH₃C(O)NH—, (CH₃)₂NC(O)—, CH₃OC(O)—, (CH₃)C(O)N(CH₃)—,HOCH₂CH₂C(O)NH—, CH₃OCH₂CH₂NHC(O)NH—, CH₃SO₂CH₂CH₂NHC(O)—,CH₃CH₂NHC(O)NH—, CH₃OC(O)NH—, morpholin-4-yl-CO—,pyrrolidin-1-yl-CH₂CH₂NHC(O)—, pyridin-2-yl, tetrahydrofuran-2-yl-CH₂O—,pyrrolidin-1-yl-CH₂CH₂O—, tetrazol-5-yl, 1-(2-cyanoethyl)-tetrazol-5-yl,pyrazol-1-yl, pyrazol-3-yl, pyrazol-4-yl, 1-methyl-pyrazol-3-yl,1-methyl-pyrrol-4-yl-C(O)NH—, 5-methyl-1,3,4-oxadiazol-2-yl, or5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl;

R⁴ is fluoro, chloro, methyl, or trifluoromethyl;

R⁵ is H or methyl;

A is furyl, thienyl, oxazolyl, isoxazolyl, thiazolyl, 1, 2,4-oxadiazolyl, 1, 3, 4-oxadiazolyl, pyrrolyl, pyrazolyl, imidazolyl, 1,2, 3-triazolyl, 1, 2, 4-triazolyl, tetrazolyl, piperidinyl,pyrrolidinyl, phenyl or pyridyl;

m is 0 or m is 1 and R^(A) is methyl;

L is O, S, N(CH₃), CH₂, CH₂CH₂, CH(CH₃), —(R)CH(CH₃), CF₂, CH₂O,CH₂N(CH₃), or CH(OH); and

B is thien-2-yl, 5-methyl-thien-2-yl, pyrazol-1-yl,3,5-dimethylpyrazol-1-yl, 4-methylpyrazol-1-yl,3,5-dimethylisoxazol-4-yl, tetrahydropyran-3-yl, tetrahydrofuran-2-yl,morpholin-4-yl, pyridin-2-yl, 2-oxo-pyridin-1-yl, 6-methylpyridin-3-yl,2-methylpyrimidin-5-yl, cyclopentyl, cyclohexyl, phenyl, 2-methylphenyl,4-methylphenyl, 2-trifluoromethylphenyl, 2-fluorophenyl, 3-fluorophenyl,4-fluorophenyl, 2-iodophenyl, 3-bromophenyl, 4-bromophenyl,4-chlorophenyl, 2,5-difluorophenyl, 2,4-difluorophenyl,3,4-difluorophenyl, 3,5-difluorophenyl, 4-methoxyphenyl,2,3-difluorophenyl or 2,6-difluorophenyl;

or -L-B—R^(B) is —OCH₂CH═CH₂, —CH₂CH₂CH₂CH₂CH₃, —OCH₂CH₂CH₂CH₃,—CH₂CH₂CH₃, —CH₂CH(CH₃)₂ or —CH₂CH₂CH(CH₃)₂;

or a salt, particularly, a pharmaceutically acceptable salt thereof.

In another specific embodiment, this invention is directed to a compoundof Formula (I) wherein:

X is O, S, SO, SO₂, NH, CO, CH₂, or N(CH₃);

Y is CH₂ or CH₂CH₂;

Z¹, Z², Z³, and Z⁴ are each CH; or Z¹ is CR¹ and Z², Z³ and Z⁴ are eachCH; or Z¹, Z², and Z⁴ are each CH and Z³ is CR³; or Z¹, Z³, and Z⁴ areeach CH and Z² is CR²; or Z¹, Z², and Z³ are each CH and Z⁴ is CR⁴; orZ¹ and Z³ are CH, Z² is CR², and Z⁴ is CR⁴; or Z¹ and Z³ are both N, Z²is CH and Z⁴ is CH or CR⁴; or Z¹ is N, Z² is CR⁴ and Z³ and Z⁴ are CH;or Z³ is N, and Z², Z³ and Z⁴ are CH;

R¹ is methyl,

R² is fluoro, chloro, bromo, —CN, —CH₃, —OH, B(OH)₂, CF₃C(OH)₂—,CH₃OCH₂CH₂O—, 5H-tetrazol-5-yl, pyrazol-3-yl, or5-methyl-1,3,4-oxadiazol-2-yl;

R³ is fluoro, chloro, bromo, —OCH₃, B(OH)₂, —COOH, CH₃SO₂—,CH₃SO₂NHC(O)—, CH₃C(O)NH—, (CH₃)₂NC(O)—, CH₃OC(O)—, (CH₃)C(O)N(CH₃)—,HOCH₂CH₂C(O)NH—, CH₃OCH₂CH₂NHC(O)NH—, CH₃SO₂CH₂CH₂NHC(O)—,CH₃CH₂NHC(O)NH—, CH₃OC(O)NH—, morpholin-4-yl-CO—,pyrrolidin-1-yl-CH₂CH₂NHC(O)—, tetrahydrofuran-2-yl-CH₂O—,pyrrolidin-1-yl-CH₂CH₂O—, tetrazol-5-yl, 1-(2-cyanoethyl)-tetrazol-5-yl,pyrazol-1-yl, pyrazol-3-yl, 1-methyl-pyrazol-3-yl,1-methyl-pyrrol-4-yl-C(O)NH—, 5-methyl-1,3,4-oxadiazol-2-yl, or5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl;

R⁴ is fluoro, chloro, methyl, or trifluoromethyl;

R⁵ is H or methyl;

A is furyl, thienyl, oxazolyl, isoxazolyl, thiazolyl, 1, 2,4-oxadiazolyl, 1, 3, 4-oxadiazolyl, pyrrolyl, pyrazolyl, imidazolyl, 1,2, 3-triazolyl, 1, 2, 4-triazolyl, tetrazolyl, piperidinyl,pyrrolidinyl, phenyl or pyridyl;

m is 0 or m is 1 and R^(A) is methyl;

L is O, S, N(CH₃), CH₂, CH₂CH₂, CH(CH₃), CF₂, CH₂O, CH₂N(CH₃), orCH(OH); and

B is thien-2-yl, 5-methyl-thien-2-yl, pyrazol-1-yl,3,5-dimethylpyrazol-1-yl, 4-methylpyrazol-1-yl,3,5-dimethylisoxazol-4-yl, tetrahydrofuran-2-yl, morpholin-4-yl,pyridin-2-yl, 2-oxo-pyridin-1-yl, 6-methylpyridin-3-yl,2-methylpyrimidin-5-yl, cyclopentyl, cyclohexyl, phenyl, 2-methylphenyl,4-methylphenyl, 2-trifluoromethylphenyl, 2-fluorophenyl, 3-fluorophenyl,4-fluorophenyl, 2-iodophenyl, 3-bromophenyl, 4-bromophenyl,4-chlorophenyl, 2,5-difluorophenyl, 2,4-difluorophenyl,3,4-difluorophenyl, 3,5-difluorophenyl, or 4-methoxyphenyl;

or -L-B—R^(B) is —OCH₂CH═CH₂, —CH₂CH₂CH₂CH₂CH₃, —OCH₂CH₂CH₂CH₃,—CH₂CH₂CH₃, —CH₂CH(CH₃)₂ or —CH₂CH₂CH(CH₃)₂;

or a salt, particularly, a pharmaceutically acceptable salt thereof.

In another specific embodiment, this invention is directed to a compoundof Formula (I) wherein:

X is O, CH₂, NH or N(CH₃);

Y is CH₂ or CH₂CH₂;

Z¹, Z², Z³, and Z⁴ are each CH; or Z¹ is CR¹ and Z², Z³ and Z⁴ are eachCH; or Z¹, Z², and Z⁴ are each CH and Z³ is CR³; or Z¹, Z³, and Z⁴ areeach CH and Z² is CR²; or Z¹, Z², and Z³ are each CH and Z⁴ is CR⁴; orZ¹ and Z³ are CH, Z² is CR², and Z⁴ is CR⁴; or Z¹ and Z³ are both N, Z²is CH and Z⁴ is CH or CR⁴; or Z¹ is N, Z² is CR⁴ and Z³ and Z⁴ are CH;or Z³ is N, and Z², Z³ and Z⁴ are CH;

R¹ is methyl,

R² is chloro, bromo, —CN, —CH₃, —OH, B(OH)₂, CF₃C(OH)₂—, CH₃OCH₂CH₂O—,5H-tetrazol-5-yl, pyrazol-3-yl, or 5-methyl-1,3,4-oxadiazol-2-yl;

R³ is fluoro, chloro, bromo, —OCH₃, B(OH)₂, —COOH, CH₃SO₂—,CH₃SO₂NHC(O)—, CH₃C(O)NH—, (CH₃)₂NC(O)—, CH₃OC(O)—, (CH₃)C(O)N(CH₃)—,HOCH₂CH₂C(O)NH—, CH₃OCH₂CH₂NHC(O)NH—, CH₃SO₂CH₂CH₂NHC(O)—,CH₃CH₂NHC(O)NH—, CH₃OC(O)NH—, morpholin-4-yl-CO—,pyrrolidin-1-yl-CH₂CH₂NHC(O)—, tetrahydrofuran-2-yl-CH₂O—,pyrrolidin-1-yl-CH₂CH₂O—, tetrazol-5-yl, 1-(2-cyanoethyl)-tetrazol-5-yl,pyrazol-1-yl, pyrazol-3-yl, 1-methyl-pyrazol-3-yl,1-methyl-pyrrol-4-yl-C(O)NH—, or 5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl;

R⁴ is fluoro or methyl;

A is furyl, thienyl, oxazolyl, isoxazolyl, thiazolyl, 1, 2,4-oxadiazolyl, 1, 3, 4-oxadiazolyl, pyrrolyl, pyrazolyl, imidazolyl, 1,2, 3-triazolyl, 1, 2, 4-triazolyl, tetrazolyl, piperidinyl,pyrrolidinyl, phenyl or pyridyl;

m is 0 or m is 1 and R^(A) is methyl;

L is O, S, N(CH₃), CH₂, CH₂CH₂, CH(CH₃), CF₂, CH₂O, CH₂N(CH₃), orCH(OH); and

B is thien-2-yl, pyrazol-1-yl, 3,5-dimethylpyrazol-1-yl,4-methylpyrazol-1-yl, 3,5-dimethylisoxazol-4-yl, tetrahydrofuran-2-yl,morpholin-4-yl, pyridin-2-yl, 2-oxo-pyridin-1-yl, 6-methylpyridin-3-yl,2-methylpyrimidin-5-yl, cyclopentyl, cyclohexyl, phenyl, 2-methylphenyl,4-methylphenyl, 2-trifluoromethylphenyl, 2-fluorophenyl, 3-fluorophenyl,4-fluorophenyl, 2-iodophenyl, 3-bromophenyl, 4-bromophenyl,4-chlorophenyl, 2,5-difluorophenyl, 2,4-difluorophenyl,3,4-difluorophenyl, 3,5-difluorophenyl, or 4-methoxyphenyl;

or -L-B is —OCH₂CH═CH₂, —CH₂CH₂CH₂CH₂CH₃, —OCH₂CH₂CH₂CH₃, —CH₂CH₂CH₃, or—CH₂CH(CH₃)₂;

or a pharmaceutically acceptable salt thereof.

In another specific embodiment, this invention is directed to a compoundof Formula (I) wherein X is O or CH₂; Y is CH₂; Z¹, Z², and Z⁴ are eachCH and Z³ is CR³; or Z¹, Z³, and Z⁴ are each CH and Z² is CR²; or Z¹,Z², and Z³ are each CH and Z⁴ is CR⁴; or Z¹ and Z³ are CH, Z² is CR²,and Z⁴ is CR⁴; R² is fluoro, chloro, bromo, or —CH₃; R³ is5-methyl-1,3,4-oxadiazol-2-yl; R⁴ is fluoro; R⁵ is H or methyl; A istriazolyl; m is 0; L is CH₂; and B is cyclopentyl or phenyl; or a salt,particularly a pharmaceutically acceptable salt thereof.

The compounds of this invention contain one or more asymmetric centers(also referred to as a chiral center), such as a chiral carbon, or achiral —SO— moiety. The stereochemistry of the chiral carbon centerpresent in compounds of this invention is generally represented in thecompound names and/or in the chemical structures illustrated herein.Compounds of this invention containing one or more chiral centers may bepresent as racemic mixtures, diastereomeric mixtures, enantiomericallyenriched mixtures, diastereomerically enriched mixtures, or asenantiomerically or diastereomerically pure individual stereoisomers.

Individual stereoisomers of a compound of this invention may be resolved(or mixtures of stereoisomers may be enriched) using methods known tothose skilled in the art. For example, such resolution may be carriedout (1) by formation of diastereoisomeric salts, complexes or otherderivatives; (2) by selective reaction with a stereoisomer-specificreagent, for example by enzymatic oxidation or reduction; or (3) bygas-liquid or liquid chromatography in a chiral environment, forexample, on a chiral support such as silica with a bound chiral ligandor in the presence of a chiral solvent. The skilled artisan willappreciate that where the desired stereoisomer is converted into anotherchemical entity by one of the separation procedures described above, afurther step is required to liberate the desired form. Alternatively,specific stereoisomers may be synthesized by asymmetric synthesis usingoptically active reagents, substrates, catalysts or solvents, or byconverting one enantiomer to the other by asymmetric transformation.

The invention also includes various deuterated forms of the compounds ofthis invention, a specific example of which isN-[(3S)-7-deuterio-1-methyl-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-3-yl]-5-(phenylmethyl)-1H-pyrazole-3-carboxamide.Each available hydrogen atom attached to a carbon atom may beindependently replaced with a deuterium atom. A person of ordinary skillin the art will know how to synthesize deuterated forms of the compoundsof this invention. For example, α-deuterated α-amino acids arecommercially available or may be prepared by conventional techniques(see for example: Elemes, Y. and Ragnarsson, U. J. Chem. Soc., PerkinTrans. 1, 1996, 6, 537-40).

Employing such compounds may allow for the preparation of compounds inwhich the hydrogen atom at a chiral center is replaced with a deuteriumatom. Other commercially available deuterated starting materials may beemployed in the preparation of deuterated analogs of the compounds ofthis invention (see for example: methyl-d3-amine available from AldrichChemical Co., Milwaukee, Wis.), or they may be synthesized usingconventional techniques employing deuterated reagents (e.g. by reductionusing lithium aluminum deuteride or sodium borodeuteride or bymetal-halogen exchange followed by quenching with D₂O or methanol-d₃).

The skilled artisan will appreciate that solvates (particularly,hydrates) of a compound of Formula (I), particularly a compound of anyone of Formulas (I-IV), including solvates of salts of a compound ofFormula (I), particularly a compound of any one of Formulas (I-IV), maybe formed when solvent molecules are incorporated into the crystallinelattice during crystallization. The present invention includes withinits scope all possible stoichiometric and non-stoichiometric salt and/orhydrate forms.

When a disclosed compound or its salt is named or depicted by structure,it is to be understood that the compound or salt, including solvates(particularly, hydrates) thereof, may exist in crystalline forms,non-crystalline forms or a mixture thereof. The compound or salt, orsolvates (particularly, hydrates) thereof, may also exhibit polymorphism(i.e. the capacity to occur in different crystalline forms). Thesedifferent crystalline forms are typically known as “polymorphs.” It isto be understood that when named or depicted by structure, the disclosedcompound, or solvates (particularly, hydrates) thereof, also include allpolymorphs thereof. Polymorphs have the same chemical composition butdiffer in packing, geometrical arrangement, and other descriptiveproperties of the crystalline solid state. Polymorphs, therefore, mayhave different physical properties such as shape, density, hardness,deformability, stability, and dissolution properties. Polymorphstypically exhibit different melting points, IR spectra, and X-ray powderdiffraction patterns, which may be used for identification. One ofordinary skill in the art will appreciate that different polymorphs maybe produced, for example, by changing or adjusting the conditions usedin crystallizing/recrystallizing the compound. It is well known andunderstood to those skilled in the art that the apparatus employed,humidity, temperature, orientation of the powder crystals, and otherparameters involved in obtaining a powder X-ray diffraction (PXRD)pattern may cause some variability in the appearance, intensities, andpositions of the lines in the diffraction pattern. A powder X-raydiffraction pattern that is “substantially in accordance” with that ofthe Figure provided herein is a PXRD pattern that would be considered byone skilled in the art to represent a compound possessing the samecrystal form as the compound that provided the PXRD pattern of theFigure. For example, the PXRD pattern may be identical to that of FIG.7, or more likely it may be somewhat different. Such a PXRD pattern maynot necessarily show each of the lines of the diffraction patternspresented herein, and/or may show a slight change in appearance,intensity, or a shift in position of said lines resulting fromdifferences in the conditions involved in obtaining the data. A personskilled in the art is capable of determining if a sample of acrystalline compound has the same form as, or a different form from, aform disclosed herein by comparison of their PXRD patterns. For example,one skilled in the art can overlay a PXRD pattern of a sample of acrystalline form of anhydrous(S)-5-benzyl-N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4H-1,2,4-triazole-3-carboxamide(free base) with the PXRD pattern of FIG. 7, and using expertise andknowledge in the art, readily determine whether the PXRD pattern of thesample is substantially in accordance with the PXRD pattern of FIG. 7.If the PXRD pattern is substantially in accordance with FIG. 7, thesample form can be readily and accurately identified as having the sameform as the crystalline form of anhydrous(S)-5-benzyl-N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4H-1,2,4-triazole-3-carboxamide(free base) described herein. Similarly, a person skilled in the art iscapable of determining if a given diffraction angle (expressed in ° 20)obtained from a PXRD pattern is at about the same position as a recitedvalue.

Because of their potential use in medicine, the salts of the compoundsof Formula (I), particularly a compound of any one of Formulas (I-IV),are preferably pharmaceutically acceptable. Suitable pharmaceuticallyacceptable salts can include acid or base addition salts.

As used herein, the term “pharmaceutically acceptable” means a compoundwhich is suitable for pharmaceutical use. Salts and solvates (e.g.hydrates and hydrates of salts) of the compounds of the invention whichare suitable for use in medicine are those wherein the counterion orassociated solvent is pharmaceutically acceptable. Salts and solvateshaving non-pharmaceutically acceptable counterions or associatedsolvents are within the scope of the present invention, for example, foruse as intermediates in the preparation of other compounds of theinvention and their salts and solvates.

Salts may be prepared in situ during the final isolation andpurification of a compound of Formula (I), particularly a compound ofany one of Formulas (I-IV). If a basic compound of Formula (I-IV) isisolated as a salt, the corresponding free base form of that compoundmay be prepared by any suitable method known to the art, includingtreatment of the salt with an inorganic or organic base, suitably aninorganic or organic base having a higher pKa than the free base form ofthe compound. Similarly, if a disclosed compound containing a carboxylicacid or other acidic functional group is isolated as a salt, thecorresponding free acid form of that compound may be prepared by anysuitable method known to the art, including treatment of the salt withan inorganic or organic acid, suitably an inorganic or organic acidhaving a lower pKa than the free acid form of the compound. Thisinvention also provides for the conversion of one salt of a compound ofthis invention, e.g., a hydrochloride salt, into another salt of acompound of this invention, e.g., a sulfate salt.

Salts of the compounds of Formula (I), particularly compounds ofFormulas (I-IV), containing a basic amine or other basic functionalgroup may be prepared by any suitable method known in the art, such astreatment of the free base with an acid. Examples of pharmaceuticallyacceptable salts so formed include acetate, adipate, ascorbate,aspartate, benzenesulfonate, benzoate, camphorate, camphor-sulfonate(camsylate), caprate (decanoate), caproate (hexanoate), caprylate(octanoate), carbonate, bicarbonate, cinnamate, citrate, cyclamate,dodecylsulfate (estolate), ethane-1,2-disulfonate (edisylate),ethanesulfonate (esylate), formate, fumarate, galactarate (mucate),gentisate (2,5-dihydroxybenzoate), glucoheptonate (gluceptate),gluconate, glucuronate, glutamate, glutarate, glycerophosphorate,glycolate, hippurate, hydrobromide, hydrochloride, hydroiodide,isobutyrate, lactate, lactobionate, laurate, maleate, malate, malonate,mandelate, methanesulfonate (mesylate), naphthalene-1,5-disulfonate(napadisylate), naphthalene-sulfonate (napsylate), nicotinate, nitrate,oleate, oxalate, palmitate, pamoate, phosphate, diphosphate,proprionate, pyroglutamate, salicylate, sebacate, stearate, succinate,sulfate, tartrate, thiocyanate, p-toluenesulfonate (tosylate),undecylenate, 1-hydroxy-2-naphthoate, 2,2-dichloroacetate,2-hydroxyethanesulfonate (isethionate), 2-oxoglutarate,4-acetamidobenzoate, and 4-aminosalicylate.

Salts of the disclosed compounds containing a carboxylic acid or otheracidic functional group can be prepared by reacting with a suitablebase. Such a pharmaceutically acceptable salt may be made with a basewhich affords a pharmaceutically acceptable cation, which includesalkali metal salts (especially sodium and potassium), alkaline earthmetal salts (especially calcium and magnesium), aluminum salts andammonium salts, as well as salts made from physiologically acceptableorganic bases such as trimethylamine, triethylamine, morpholine,pyridine, piperidine, picoline, dicyclohexylamine,N,N′-dibenzylethylenediamine, 2-hydroxyethylamine,bis-(2-hydroxyethyl)amine, tri-(2-hydroxyethyl)amine, procaine,dibenzylpiperidine, dehydroabietylamine, N,N′-bisdehydroabietylamine,glucamine, N-methylglucamine, collidine, choline, quinine, quinoline,and basic amino acids such as lysine and arginine. In one embodiment,the pharmaceutically acceptable base-addition salt of a compound ofFormula (I) is a sodium salt or a potassium salt thereof.

Because the compounds of this invention are intended for use inpharmaceutical compositions it will readily be understood that they areeach preferably provided in substantially pure form, for example atleast 60% pure, more suitably at least 75% pure and preferably at least85%, especially at least 98% pure (% are on a weight for weight basis).Impure preparations of the compounds may be used for preparing the morepure forms used in the pharmaceutical compositions.

General Synthetic Methods

The compounds of this invention may be prepared using syntheticprocedures illustrated in the Schemes below or by drawing on theknowledge of a skilled organic chemist. The synthesis provided in theseSchemes are applicable for producing compounds of the invention having avariety of different R groups employing appropriate precursors, whichare suitably protected if needed, to achieve compatibility with thereactions outlined herein. Subsequent deprotection, where needed,affords compounds of the nature generally disclosed. While the Schemesare shown with compounds only of Formulas (I-IV), they are illustrativeof processes that may be used to make the compounds of the invention.

Intermediates (compounds used in the preparation of the compounds of theinvention) may also be present as salts. Thus, in reference tointermediates, the phrase “compound(s) of formula (number)” means acompound having that structural formula or a pharmaceutically acceptablesalt thereof.

(S)—N-(4-Oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)carboxamidesmay be prepared via the general method outlined in Scheme 1.Boc-L-serine can be condensed with an appropriate substituted1-fluoro-2-nitrobenzene with a base, followed by reduction of the nitrogroup to the amine and cyclisation to the Boc protected(S)-3-amino-2,3-dihydrobenzo[b][1,4]oxazepin-4(5H)-one using an amidecoupling agent. The Boc protecting group can be removed using acidicconditions and the resulting free amine can be coupled to theappropriate acid using an amide coupling agent. The Boc protected(S)-3-amino-2,3-dihydrobenzo[b][1,4]oxazepin-4(5H)-one can also bemethylated to give the Boc protected(S)-3-amino-5-methyl-2,3-dihydrobenzo[b][1,4]oxazepin-4(5H)-one, whichcan then be deprotected using acidic conditions, and the resulting freeamine can be coupled to an appropriate acid using an amide couplingagent.

(R)—N-(4-Oxo-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepin-3-yl)carboxamidesmay be prepared via the general method outlined in Scheme 2.Boc-L-cysteine can be condensed with an appropriate substituted1-fluoro-2-nitrobenzene with a base, followed by reduction of the nitrogroup to the amine and cyclisation to the Boc protected(R)-3-amino-2,3-dihydrobenzo[b][1,4]thiazepin-4(5H)-one using an amidecoupling agent. The Boc protecting group can be removed using acidicconditions and the resulting free amine can be coupled to an appropriateacid using an amide coupling agent. The Boc protected(R)-3-amino-2,3-dihydrobenzo[b][1,4]thiazepin-4(5H)-one can also bemethylated to give the Boc protected(R)-3-amino-5-methyl-2,3-dihydrobenzo[b][1,4]thiazepin-4(5H)-one, whichcan then be deprotected using acidic conditions, and the resulting freeamine can be coupled to an appropriate acid using an amide couplingagent.

(S)—N-(2-Oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-yl)carboxamidesmay be prepared via the general method outlined in Scheme 3.3-Aminoalanine can be condensed with the appropriate substituted1-fluoro-2-nitrobenzene with a base, followed by reduction of the nitrogroup to the amine and cyclisation to the Boc protected(S)-3-amino-4,5-dihydro-1H-benzo[b][1,4]diazepin-2(3H)-one using anamide coupling agent. The Boc protecting group can be removed usingacidic conditions and the resulting free amine can be coupled to theappropriate acid using an amide coupling agent. The Boc protected(S)-3-amino-4,5-dihydro-1H-benzo[b][1,4]diazepin-2(3H)-one can also bemethylated with methyl iodide using sodium hydride as base to give theBoc protected(S)-3-amino-1-methyl-4,5-dihydro-1H-benzo[b][1,4]diazepin-2(3H)-one,which can then be deprotected using acidic conditions, and the resultingfree amine can be coupled to the appropriate acid using an amidecoupling agent. Alternatively, the Boc protected(S)-3-amino-4,5-dihydro-1H-benzo[b][1,4]diazepin-2(3H)-one can also bemethylated with methyl iodide using potassium carbonate as base inethanol to give the Boc protected(S)-3-amino-5-methyl-4,5-dihydro-1H-benzo[b][1,4]diazepin-2(3H)-one,which can then be deprotected using acidic conditions, and the resultingfree amine can be coupled to the appropriate acid using an amidecoupling agent.

(S)—N-(6-Oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-7-yl)carboxamidesmay be prepared via the general method outlined in Scheme 4.Boc-L-serine can be condensed with 4,6-dichloropyrimidin-5-amine in thepresence of a base such as triethylamine, followed by cyclisation to theBoc protected(S)-7-amino-4-chloro-8,9-dihydro-5H-pyrimido[4,5-b][1,4]diazepin-6(7H)-oneusing an amide coupling agent. The chloride can be removed by reductionusing hydrogenation with a palladium/carbon catalyst. The Boc protectinggroup can then be removed using acidic conditions and the resulting freeamine can be coupled to the appropriate acid using an amide couplingagent. Alternatively, the Boc protected(S)-7-amino-8,9-dihydro-5H-pyrimido[4,5-b][1,4]diazepin-6(7H)-one can bemethylated in the presence of a base, deprotected using acidicconditions, and the resulting free amine can be coupled to theappropriate acid using an amide coupling agent to yield(S)—N-(5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-7-yl)carboxamides(Scheme 4, R═H). If the chloride is not removed, then this sequence canbe repeated to yield the corresponding(S)—N-(4-chloro-5-methyl-6-oxo-6,7, 8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-7-yl)carboxamides (Scheme 4, R═C₁).

(S)—N-(2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-3-yl) carboxamides maybe prepared via the general method outlined in Scheme 5. Theappropriately substituted tetralone can be converted to the1,3,4,5-tetrahydro-1-benzazepin-2-one via either an acid-mediatedSchmidt reaction with sodium azide, or Beckmann rearrangement of thecorresponding ketoximes formed from reaction with hydroxylamine. The1,3,4,5-tetrahydro-1-benzazepin-2-one can then be converted to theα-iodobenzlactam by iodotrimethylsilane-mediate iodination, subsequentlyconverted to the α-azidobenzlactam with sodium azide, and following aStaudinger reduction with triphenylphosphine yields theα-aminobenzlactam. A racemization/resolution of the α-aminobenzlactamcan be accomplished using L-pyroglutamic acid and 5-nirosalicylaldehydeto yield the (S)-3-amino-4,5-dihydro-1H-benzo[b]azepin-2(3H)-one asdescribed by Armstrong et. al. in Tetrahedron Letters 1994, pages3239-42. This amine can then be coupled to the appropriate acid using anamide coupling agent. Alternatively the amine can protected with a Bocprotecting group, then methylated at the lactam nitrogen with methyliodide, followed by deprotected using acidic conditions. The resultingfree amine can be coupled to the appropriate acid using an amidecoupling agent.

5-Substituted-4H-1,2,4-triazole-3-carboxylic acids may be prepared viathe general method outlined in Scheme 6. The appropriately substitutedacetohydrazide is condensed with ethyl 2-ethoxy-2-iminoacetate inethanol. The resulting ethyl 2-amino-2-(2-substituted hydrazono)acetateis then heated neat or in a high boiling solvent such as xylenesresulting in cyclization to the5-substituted-4H-1,2,4-triazole-3-carboxylic ethyl ester. This can thenby hydrolyzed using aqueous base, for example lithium hydroxide in THFand water.

5-Benzyl-1H-pyrazole-3-carboxylic acids can be prepared following theroute shown in Scheme 7. The appropriately substituted benzyl methylketone is condensed with diethyl oxalate in the presence of a base suchas potassium tert-butoxide in ethanol. The resulting ethyl5-(substituted-phenyl)-2,4-dioxopentanoate is then condensed withhydrazine in ethanol resulting in cyclization to the ethyl 5-substitutedbenzyl-1H-pyrazole-3-carboxylate. This can then by hydrolyzed usingaqueous base, for example lithium hydroxide in THF and water.

5-Methyl-1-substituted-1H-pyrazole-3-carboxylic acids can be preparedfollowing the route shown in Scheme 8. Ethyl3-methyl-1H-pyrazole-5-carboxylate is alkylated in the presence of abase such as potassium hydroxide with the appropriate alkylating agent,such as an alkyl or arylbromide, to give a mixture of desired ethyl5-methyl-1-propyl-1H-pyrazole-3-carboxylate and undesired regioisomerethyl 3-methyl-1-substituted-1H-pyrazole-5-carboxylate ethyl oxalate.The ethyl 5-methyl-1-substituted-1H-pyrazole-3-carboxylates can beisolated using chromatography and then hydrolyzed using aqueous base,for example lithium hydroxide in THF and water to yield5-methyl-1-propyl-1H-pyrazole-3-carboxylic acids.

The compounds of this invention may be particularly useful for thetreatment of RIP1 kinase-mediated diseases or disorders. Such RIP1kinase-mediated diseases or disorders are diseases or disorders that aremediated by activation of RIP1 kinase, and as such, are diseases ordisorders where inhibition of RIP1 kinase would provide benefit. Thecompounds of this invention may be particularly useful for the treatmentof diseases/disorders which are likely to be regulated at least in partby programmed necrosis, particularly inflammatory bowel disease(including Crohn's disease and ulcerative colitis), psoriasis, retinaldetachment, retinitis pigmentosa, macular degeneration, pancreatitis,atopic dermatitis, arthritis (including rheumatoid arthritis,spondyloarthritis, gout, SoJIA), systemic lupus erythematosus (SLE),Sjogren's syndrome, systemic scleroderma, anti-phospholipid syndrome(APS), vasculitis, osteoarthritis, liver damage/diseases (non-alcoholsteatohepatitis, alcohol steatohepatitis, autoimmune hepatitisautoimmune hepatobiliary diseases, primary sclerosing cholangitis(PSC)), nephritis, Celiac disease, autoimmune ITP, transplant rejection,ischemia reperfusion injury of solid organs, sepsis, systemicinflammatory response syndrome (SIRS), cerebrovascular accident (CVA),myocardial infarction (MI), Huntington's disease, Alzheimer's disease,Parkinson's disease, allergic diseases (including asthma and atopicdermatitis), multiple sclerosis, type I diabetes, Wegener'sgranulomatosis, pulmonary sarcoidosis, Behcet's disease, interleukin-1converting enzyme (ICE, also known as caspase-1) associated feversyndrome, chronic obstructive pulmonary disease (COPD), tumor necrosisfactor receptor-associated periodic syndrome (TRAPS) and peridontitis.

The compounds of this invention may be particularly useful for thetreatment of diseases/disorders which are likely to be regulated atleast in part by programmed necrosis, apoptosis or the production ofinflammatory cytokines, particularly inflammatory bowel disease(including Crohn's disease and ulcerative colitis), psoriasis, retinaldetachment, retinitis pigmentosa, macular degeneration, pancreatitis,atopic dermatitis, arthritis (including rheumatoid arthritis,spondyloarthritis, gout, systemic onset juvenile idiopathic arthritis(SoJIA), psoriatic arthritis), systemic lupus erythematosus (SLE),Sjogren's syndrome, systemic scleroderma, anti-phospholipid syndrome(APS), vasculitis, osteoarthritis, liver damage/diseases (non-alcoholsteatohepatitis, alcohol steatohepatitis, autoimmune hepatitis,autoimmune hepatobiliary diseases, primary sclerosing cholangitis (PSC),acetaminophen toxicity, hepatotoxicity), kidney damage/injury(nephritis, renal transplant, surgery, administration of nephrotoxicdrugs e.g. cisplatin, acute kidney injury(AKI)) Celiac disease,autoimmune idiopathic thrombocytopenic purpura (autoimmune ITP),transplant rejection, ischemia reperfusion injury of solid organs,sepsis, systemic inflammatory response syndrome (SIRS), cerebrovascularaccident (CVA, stroke), myocardial infarction (MI), atherosclerosis,Huntington's disease, Alzheimer's disease, Parkinson's disease,Amyotrophic lateral sclerosis (ALS), allergic diseases (including asthmaand atopic dermatitis), multiple sclerosis, type I diabetes, Wegener'sgranulomatosis, pulmonary sarcoidosis, Behcet's disease, interleukin-1converting enzyme (ICE, also known as caspase-1) associated feversyndrome, chronic obstructive pulmonary disease (COPD), tumor necrosisfactor receptor-associated periodic syndrome (TRAPS), peridontitis,NEMO-deficiency syndrome (NF-kappa-B essential modulator gene (alsoknown as IKK gamma or IKKG) deficiency syndrome), HOIL-1 deficiency((also known as RBCK1) heme-oxidized IRP2 ubiquitin ligase-1deficiency), linear ubiquitin chain assembly complex (LUBAC) deficiencysyndrome, hematological and solid organ malignancies, bacterialinfections and viral infections (such as tuberculosis and influenza),and Lysosomal storage diseases (particularly, Gaucher Disease, andincluding GM2 Gangliosidosis, Alpha-mannosidosis,Aspartylglucosaminuria, Cholesteryl Ester storage disease, ChronicHexosaminidase A Deficiency, Cystinosis, Danon disease, Fabry disease,Farber disease, Fucosidosis, Galactosialidosis, GM1 gangliosidosis,Mucolipidosis, Infantile Free Sialic Acid Storage Disease, JuvenileHexosaminidase A Deficiency, Krabbe disease, Lysosomal acid lipasedeficiency, Metachromatic Leukodystrophy, Mucopolysaccharidosesdisorders, Multiple sulfatase deficiency, Niemann-Pick Disease, NeuronalCeroid Lipofuscinoses, Pompe disease, Pycnodysostosis, Sandhoff disease,Schindler disease, Sialic Acid Storage Disease, Tay-Sachs and Wolmandisease).

The treatment of the above-noted diseases/disorders may concern, morespecifically, the amelioration of organ injury or damage sustained as aresult of the noted diseases. For example, the compounds of thisinvention may be particularly useful for amelioration of brain tissueinjury or damage following ischemic brain injury or traumatic braininjury, or for amelioration of heart tissue injury or damage followingmyocardial infarction, or for amelioration of brain tissue injury ordamage associated with Huntington's disease, Alzheimer's disease orParkinson's disease, or for amelioration of liver tissue injury ordamage associated with non-alcohol steatohepatitis, alcoholsteatohepatitis, autoimmune hepatitis autoimmune hepatobiliary diseases,or primary sclerosing cholangitis. In addition, the treatment ofdiseases/disorders selected from those described herein may concern,more specifically, the amelioration of liver tissue injury or damageassociated with overdose of acetaminophen, or for amelioration of kidneytissue injury or damage following renal transplant or the administrationof nephrotoxic drugs or substances e.g. cisplatin.

The compounds of this invention may be particularly useful for thetreatment of inflammatory bowel disease (including Crohn's disease andulcerative colitis), psoriasis, retinal detachment, retinitispigmentosa, arthritis (including rheumatoid arthritis,spondyloarthritis, gout, and SoJIA), transplant rejection, ischemiareperfusion injury of solid organs, multiple sclerosis, and/or tumornecrosis factor receptor-associated periodic syndrome. Morespecifically, the compounds of this invention may be particularly usefulfor the treatment of inflammatory bowel disease (including Crohn'sdisease and ulcerative colitis), psoriasis, retinal detachment,retinitis pigmentosa, arthritis (including rheumatoid arthritis,spondyloarthritis, gout, and systemic onset juvenile idiopathicarthritis (SoJIA)), transplant rejection, and/or ischemia reperfusioninjury of solid organs.

Treatment of RIP1-mediated disease conditions, or more broadly,treatment of immune mediated disease, such as, but not limited to,allergic diseases, autoimmune diseases, prevention of transplantrejection and the like, may be achieved using a compound of thisinvention as a monotherapy, or in dual or multiple combination therapy,particularly for the treatment of refractory cases, such as incombination with other anti-inflammatory and/or anti-TNF agents, whichmay be administered in therapeutically effective amounts as is known inthe art.

The compounds of any one of Formulas (I-IV) and pharmaceuticallyacceptable salts thereof may be employed alone or in combination withother therapeutic agents.

Combination therapies according to the present invention thus comprisethe administration of at least one compound of any one of Formulas(I-IV) or a pharmaceutically acceptable salt thereof, and at least oneother therapeutically active agent. Preferably, combination therapiesaccording to the present invention comprise the administration of atleast one compound of any one of Formulas (I-IV) or a pharmaceuticallyacceptable salt thereof, and at least one other therapeutically activeagent. The compound(s) of any one of Formulas (I-IV) andpharmaceutically acceptable salts thereof, and the other therapeuticallyactive agent(s) may be administered together in a single pharmaceuticalcomposition or separately and, when administered separately this mayoccur simultaneously or sequentially in any order. The amounts of thecompound(s) of any one of Formulas (I-IV) and pharmaceuticallyacceptable salts thereof, and the other therapeutically active agent(s)and the relative timings of administration will be selected in order toachieve the desired combined therapeutic effect. Thus in a furtheraspect, there is provided a combination comprising a compound of any oneof Formulas (I-IV) or a pharmaceutically acceptable salt thereof,together with one or more other therapeutically active agents. In oneaspect, there is provided a combination comprising(S)-5-benzyl-N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4H-1,2,4-triazole-3-carboxamide,or a pharmaceutically acceptable salt thereof, together with one or moreother therapeutically active agents. In another aspect, there isprovided a combination comprising(S)-5-benzyl-N-(7-chloro-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-3-yl)-4H-1,2,4-triazole-3-carboxamide,or a pharmaceutically acceptable salt thereof, together with one or moreother therapeutically active agents. Thus in one aspect of thisinvention, a compound of any one of Formulas (I-IV) or apharmaceutically acceptable salt thereof, and a pharmaceuticalcomposition comprising a compound of any one of Formulas (I-IV) or apharmaceutically acceptable salt thereof, may be used in combinationwith or include one or more other therapeutic agents, for example ananti-inflammatory agent and/or an anti-TNF agent.

For example, the compounds of this invention may be administered incombination with other anti-inflammatory agents for any of theindications above, including oral or topical corticosteroids (such asprednisone (Deltasone®) and bundesonide), anti-TNF agents (includinganti-TNF biologic agents), 5-aminosalicyclic acid and mesalaminepreparations, hydroxycloroquine, thiopurines (azathioprin,mercaptopurin), methotrexate, cyclophosphamide, cyclosporine, JAKinhibitors (tofacitinib), anti-IL6 biologics, anti-IL1 or IL12 or IL23biologics(ustekinumab(Stelara®)), anti-integrin agents(natalizumab(Tysabri®)), anti-CD20 or CD4 biologics and other cytokine inhibitors orbiologics to T-cell or B-cell receptors or interleukins.

The compounds of this invention may be administered in combination withother anti-inflammatory agents for any of the indications above,including oral or topical corticosteroids (such as prednisone(Deltasone®) and bundesonide), anti-TNF agents (including anti-TNFbiologic agents), 5-aminosalicyclic acid and mesalamine preparations,hydroxycloroquine, thiopurines (azathioprin, mercaptopurin),methotrexate, cyclophosphamide, cyclosporine, calcineurin inhibitors(cyclosporine, pimecrolimus, tacrolimus), mycophenolic acid (CellCept®),mTOR inhibitors (temsirolimus, everolimus), JAK inhibitors(tofacitinib), (Xeljan®)), Syk inhibitors (fostamatinib), anti-IL6biologics, anti-IL1 (anakinra (Kineret®), canakinumab (Ilaris®),rilonacept (Arcalyst®)), anti-IL12 and IL23 biologics(ustekinumab(Stelara®)), anti-IL17 biologics (secukinumab), anti-CD22(epratuzumab), anti-integrin agents(natalizumab (Tysabri®)), vedolizumab(Entyvio®)), anti-IFNa (sifalimumab), anti-CD20 or CD4 biologics andother cytokine inhibitors or biologics to T-cell or B-cell receptors orinterleukins.

Examples of suitable anti-inflammatory biologic agents include Actemra®(anti-IL6R mAb), anti-CD20 mAbs (rituximab (Rituxan®) and ofatumumab(Arzerra®)), abatacept (Orencia®), anakinra (Kineret®), ustekinumab(Stelara®), and belimumab (Benlysta®). Examples of other suitableanti-inflammatory biologic agents include Actemra® (tocilizumab,anti-IL6R mAb), anti-CD20 mAbs (rituximab (Rituxan®) and ofatumumab(Arzerra®)), abatacept (Orencia®), anakinra (Kineret®), Canakinumab(Ilaris®), rilonacept (Arcalyst®), secukinumab, epratuzumab,sifalimumab, ustekinumab (Stelara®), and belimumab (Benlysta®). Examplesof suitable anti-TNF agents biologic agents include etanecerpt(Enbrel®), adalimumab (Humira®), infliximab (Remicade®), certolizumab(Cimzia®), and golimumab (Simponi®).

Accordingly, one embodiment of this invention is directed to a method ofinhibiting RIP1 kinase comprising contacting a cell with a compound ofthe invention. In another embodiment, the invention is directed to amethod of treating a RIP1 kinase-mediated disease or disorder(specifically, a disease or disorder recited herein) comprisingadministering a therapeutically effective amount of a compound ofFormula (I), particularly a compound of any one of Formulas (I-IV), or asalt, particularly a pharmaceutically acceptable salt thereof, to ahuman in need thereof.

In one specific embodiment, the invention is directed to a method oftreating a RIP1 kinase-mediated disease or disorder (specifically, adisease or disorder recited herein) comprising administering atherapeutically effective amount of(S)-5-benzyl-N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4H-1,2,4-triazole-3-carboxamide,or a pharmaceutically acceptable salt thereof, to a human in needthereof. In another specific embodiment, the invention is directed to amethod of treating a RIP1 kinase-mediated disease or disorder(specifically, a disease or disorder recited herein) comprisingadministering a therapeutically effective amount of(S)-5-benzyl-N-(7-chloro-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-3-yl)-4H-1,2,4-triazole-3-carboxamide,or a pharmaceutically acceptable salt thereof, to a human in needthereof.

Specifically, this invention provides a compound of the invention foruse in therapy. This invention also provides a compound of Formula (I),particularly a compound of any one of Formulas (I-IV), or apharmaceutically acceptable salt thereof, for use in therapy. Thisinvention particularly provides a compound of Formula (I), particularlya compound of any one of Formulas (I-IV), or a pharmaceuticallyacceptable salt thereof, for use in the treatment of a RIP1kinase-mediated disease or disorder (for example, a disease or disorderrecited herein).

Specifically, this invention provides a compound described herein, or apharmaceutically acceptable salt thereof, for use in therapy. Morespecifically, this invention provides(S)-5-benzyl-N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4H-1,2,4-triazole-3-carboxamide,or a pharmaceutically acceptable salt thereof, for use in therapy. Thisinvention further provides(S)-5-benzyl-N-(7-chloro-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-3-yl)-4H-1,2,4-triazole-3-carboxamide,or a pharmaceutically acceptable salt thereof, for use in therapy.

In another embodiment, this invention provides a compound of theinvention for use in the treatment of a RIP1 kinase-mediated disease ordisorder. Specifically, this invention provides a compound describedherein, or a pharmaceutically acceptable salt thereof, for use in thetreatment of a RIP1 kinase-mediated disease or disorder. In anotherembodiment, this invention provides a compound of Formula (I),particularly a compound of any one of Formulas (I-IV), or apharmaceutically acceptable salt thereof, for use in the treatment ofdiseases/disorders which are likely to be regulated at least in part byprogrammed necrosis, apoptosis or the production of inflammatorycytokines, particularly inflammatory bowel disease (including Crohn'sdisease and ulcerative colitis), psoriasis, retinal detachment,retinitis pigmentosa, macular degeneration, pancreatitis, atopicdermatitis, arthritis (including rheumatoid arthritis,spondyloarthritis, gout, systemic onset juvenile idiopathic arthritis(SoJIA)), systemic lupus erythematosus (SLE), Sjogren's syndrome,systemic scleroderma, anti-phospholipid syndrome (APS), vasculitis,osteoarthritis, liver damage/diseases (non-alcohol steatohepatitis,alcohol steatohepatitis, autoimmune hepatitis, autoimmune hepatobiliarydiseases, primary sclerosing cholangitis (PSC)), nephritis, Celiacdisease, autoimmune idiopathic thrombocytopenic purpura (autoimmuneITP), transplant rejection, ischemia reperfusion injury of solid organs,sepsis, systemic inflammatory response syndrome (SIRS), cerebrovascularaccident (CVA, stroke), myocardial infarction (MI), atherosclerosis,Huntington's disease, Alzheimer's disease, Parkinson's disease,Amyotrophic lateral sclerosis (ALS), allergic diseases (including asthmaand atopic dermatitis), multiple sclerosis, type I diabetes, Wegener'sgranulomatosis, pulmonary sarcoidosis, Behcet's disease, interleukin-1converting enzyme (ICE, also known as caspase-1) associated feversyndrome, chronic obstructive pulmonary disease (COPD), tumor necrosisfactor receptor-associated periodic syndrome (TRAPS), peridontitis,NEMO-deficiency syndrome (NF-kappa-B essential modulator gene (alsoknown as IKK gamma or IKKG) deficiency syndrome), HOIL-1 deficiency((also known as RBCK1) heme-oxidized IRP2 ubiquitin ligase-1deficiency), linear ubiquitin chain assembly complex (LUBAC) deficiencysyndrome, hematological and solid organ malignancies, bacterialinfections and viral infections (such as tuberculosis and influenza),and Lysosomal storage diseases (particularly, Gaucher Disease, andincluding GM2 Gangliosidosis, Alpha-mannosidosis,Aspartylglucosaminuria, Cholesteryl Ester storage disease, ChronicHexosaminidase A Deficiency, Cystinosis, Danon disease, Fabry disease,Farber disease, Fucosidosis, Galactosialidosis, GM1 gangliosidosis,Mucolipidosis, Infantile Free Sialic Acid Storage Disease, JuvenileHexosaminidase A Deficiency, Krabbe disease, Lysosomal acid lipasedeficiency, Metachromatic Leukodystrophy, Mucopolysaccharidosesdisorders, Multiple sulfatase deficiency, Niemann-Pick Disease, NeuronalCeroid Lipofuscinoses, Pompe disease, Pycnodysostosis, Sandhoff disease,Schindler disease, Sialic Acid Storage Disease, Tay-Sachs and Wolmandisease), wherein treatment of the above-noted diseases/disorders mayconcern, more specifically, the amelioration of organ injury or damagesustained as a result of the noted diseases.

In another embodiment, this invention provides a compound of Formula(I), or a pharmaceutically acceptable salt thereof, for use in thetreatment of inflammatory bowel disease. In another embodiment, thisinvention provides a compound of Formula (I), or a pharmaceuticallyacceptable salt thereof, for use in the treatment of Crohn's disease. Inanother embodiment, this invention provides a compound of Formula (I),or a pharmaceutically acceptable salt thereof, for use in the treatmentof ulcerative colitis. In another embodiment, this invention provides acompound of Formula (I), or a pharmaceutically acceptable salt thereof,for use in the treatment of psoriasis. In another embodiment, thisinvention provides a compound of Formula (I), or a pharmaceuticallyacceptable salt thereof, for use in the treatment of retinal detachment.In another embodiment, this invention provides a compound of Formula(I), or a pharmaceutically acceptable salt thereof, for use in thetreatment of retinitis pigmentosa. In another embodiment, this inventionprovides a compound of Formula (I), or a pharmaceutically acceptablesalt thereof, for use in the treatment of arthritis. In anotherembodiment, this invention provides a compound of Formula (I), or apharmaceutically acceptable salt thereof, for use in the treatment ofrheumatoid arthritis. In another embodiment, this invention provides acompound of Formula (I), or a pharmaceutically acceptable salt thereof,for use in the treatment of spondyloarthritis. In another embodiment,this invention provides a compound of Formula (I), or a pharmaceuticallyacceptable salt thereof, for use in the treatment of gout. In anotherembodiment, this invention provides a compound of Formula (I), or apharmaceutically acceptable salt thereof, for use in the treatment ofsystemic onset juvenile idiopathic arthritis. In another embodiment,this invention provides a compound of Formula (I), or a pharmaceuticallyacceptable salt thereof, for use in the treatment of transplantrejection. In another embodiment, this invention provides a compound ofFormula (I), or a pharmaceutically acceptable salt thereof, for use inthe treatment of ischemia reperfusion injury of solid organs.

This invention specifically provides for the use of a compound ofFormula (I), particularly a compound of any one of Formulas (I-IV), or apharmaceutically acceptable salt thereof, as an active therapeuticsubstance. More specifically, this provides for the use of the compoundsdescribed herein for the treatment of a RIP1 kinase-mediated disease ordisorder. Accordingly, the invention provides for the use of a compoundof Formula (I), particularly a compound of any one of Formulas (I-IV),or a pharmaceutically acceptable salt thereof, as an active therapeuticsubstance in the treatment of a human in need thereof with a RIP1kinase-mediated disease or disorder.

The invention further provides for the use of a compound of Formula (I),particularly a compound of any one of Formulas (I-IV), or a saltthereof, particularly a pharmaceutically acceptable salt thereof, in themanufacture of a medicament for use in the treatment of a RIP1kinase-mediated disease or disorder, for example the diseases anddisorders recited herein. Specifically, the invention also provides forthe use of a compound described herein, or a pharmaceutically acceptablesalt thereof, in the manufacture of a medicament for use in thetreatment of a RIP1 kinase-mediated disease or disorder, for example thediseases and disorders recited herein. More specifically, the inventionalso provides for the use of(S)-5-benzyl-N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4H-1,2,4-triazole-3-carboxamide,or a pharmaceutically acceptable salt thereof, in the manufacture of amedicament for use in the treatment of a RIP1 kinase-mediated disease ordisorder, for example the diseases and disorders recited herein. Theinvention further provides for the use of(S)-5-benzyl-N-(7-chloro-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-3-yl)-4H-1,2,4-triazole-3-carboxamide,or a pharmaceutically acceptable salt thereof, in the manufacture of amedicament for use in the treatment of a RIP1 kinase-mediated disease ordisorder, for example the diseases and disorders recited herein.Accordingly, the invention provides for the use of a compound of Formula(I), particularly a compound of any one of Formulas (I-IV), or apharmaceutically acceptable salt thereof, in the manufacture of amedicament for use in the treatment of a human in need thereof with aRIP1 kinase-mediated disease or disorder.

In one embodiment, this invention provides for the use of a compound ofFormula (I), particularly a compound of any one of Formulas (I-IV), or apharmaceutically acceptable salt thereof, in the manufacture of amedicament for use in the treatment of diseases/disorders which arelikely to be regulated at least in part by programmed necrosis,apoptosis or the production of inflammatory cytokines, particularlyinflammatory bowel disease (including Crohn's disease and ulcerativecolitis), psoriasis, retinal detachment, retinitis pigmentosa, maculardegeneration, pancreatitis, atopic dermatitis, arthritis (includingrheumatoid arthritis, spondyloarthritis, gout, systemic onset juvenileidiopathic arthritis (SoJIA)), systemic lupus erythematosus (SLE),Sjogren's syndrome, systemic scleroderma, anti-phospholipid syndrome(APS), vasculitis, osteoarthritis, liver damage/diseases (non-alcoholsteatohepatitis, alcohol steatohepatitis, autoimmune hepatitis,autoimmune hepatobiliary diseases, primary sclerosing cholangitis(PSC)), nephritis, Celiac disease, autoimmune idiopathicthrombocytopenic purpura (autoimmune ITP), transplant rejection,ischemia reperfusion injury of solid organs, sepsis, systemicinflammatory response syndrome (SIRS), cerebrovascular accident (CVA,stroke), myocardial infarction (MI), atherosclerosis, Huntington'sdisease, Alzheimer's disease, Parkinson's disease, Amyotrophic lateralsclerosis (ALS), allergic diseases (including asthma and atopicdermatitis), multiple sclerosis, type I diabetes, Wegener'sgranulomatosis, pulmonary sarcoidosis, Behcet's disease, interleukin-1converting enzyme (ICE, also known as caspase-1) associated feversyndrome, chronic obstructive pulmonary disease (COPD), tumor necrosisfactor receptor-associated periodic syndrome (TRAPS), peridontitis,NEMO-deficiency syndrome (NF-kappa-B essential modulator gene (alsoknown as IKK gamma or IKKG) deficiency syndrome), HOIL-1 deficiency((also known as RBCK1) heme-oxidized IRP2 ubiquitin ligase-1deficiency), linear ubiquitin chain assembly complex (LUBAC) deficiencysyndrome, hematological and solid organ malignancies, bacterialinfections and viral infections (such as tuberculosis and influenza),and Lysosomal storage diseases (particularly, Gaucher Disease, andincluding GM2 Gangliosidosis, Alpha-mannosidosis,Aspartylglucosaminuria, Cholesteryl Ester storage disease, ChronicHexosaminidase A Deficiency, Cystinosis, Danon disease, Fabry disease,Farber disease, Fucosidosis, Galactosialidosis, GM1 gangliosidosis,Mucolipidosis, Infantile Free Sialic Acid Storage Disease, JuvenileHexosaminidase A Deficiency, Krabbe disease, Lysosomal acid lipasedeficiency, Metachromatic Leukodystrophy, Mucopolysaccharidosesdisorders, Multiple sulfatase deficiency, Niemann-Pick Disease, NeuronalCeroid Lipofuscinoses, Pompe disease, Pycnodysostosis, Sandhoff disease,Schindler disease, Sialic Acid Storage Disease, Tay-Sachs and Wolmandisease), wherein treatment of the above-noted diseases/disorders mayconcern, more specifically, the amelioration of organ injury or damagesustained as a result of the noted diseases.

In another embodiment, this invention provides for the use of a compoundof Formula (I), or a pharmaceutically acceptable salt thereof, in themanufacture of a medicament for use in the treatment of inflammatorybowel disease. In another embodiment, this invention provides for theuse of a compound of Formula (I), or a pharmaceutically acceptable saltthereof, in the manufacture of a medicament for use in the treatment ofCrohn's disease. In another embodiment, this invention provides for theuse of a compound of Formula (I), or a pharmaceutically acceptable saltthereof, in the manufacture of a medicament for use in the treatment ofulcerative colitis. In another embodiment, this invention provides forthe use of a compound of Formula (I), or a pharmaceutically acceptablesalt thereof, in the manufacture of a medicament for use in thetreatment of psoriasis. In another embodiment, this invention providesfor the use of a compound of Formula (I), or a pharmaceuticallyacceptable salt thereof, in the manufacture of a medicament for use inthe treatment of retinal detachment. In another embodiment, thisinvention provides for the use of a compound of Formula (I), or apharmaceutically acceptable salt thereof, in the manufacture of amedicament for use in the treatment of retinitis pigmentosa. In anotherembodiment, this invention provides for the use of a compound of Formula(I), or a pharmaceutically acceptable salt thereof, in the manufactureof a medicament for use in the treatment of arthritis. In anotherembodiment, this invention provides for the use of a compound of Formula(I), or a pharmaceutically acceptable salt thereof, in the manufactureof a medicament for use in the treatment of rheumatoid arthritis. Inanother embodiment, this invention provides for the use of a compound ofFormula (I), or a pharmaceutically acceptable salt thereof, in themanufacture of a medicament for use in the treatment ofspondyloarthritis. In another embodiment, this invention provides forthe use of a compound of Formula (I), or a pharmaceutically acceptablesalt thereof, in the manufacture of a medicament for use in thetreatment of gout. In another embodiment, this invention provides forthe use of a compound of Formula (I), or a pharmaceutically acceptablesalt thereof, in the manufacture of a medicament for use in thetreatment of systemic onset juvenile idiopathic arthritis. In anotherembodiment, this invention provides for the use of a compound of Formula(I), or a pharmaceutically acceptable salt thereof, in the manufactureof a medicament for use in the treatment of transplant rejection. Inanother embodiment, this invention provides for the use of a compound ofFormula (I), or a pharmaceutically acceptable salt thereof, in themanufacture of a medicament for use in the treatment of ischemiareperfusion injury of solid organs.

A therapeutically “effective amount” is intended to mean that amount ofa compound that, when administered to a patient in need of suchtreatment, is sufficient to effect treatment, as defined herein. Thus,e.g., a therapeutically effective amount of a compound of Formula (I),particularly a compound of any one of Formulas (I-IV), or apharmaceutically acceptable salt thereof, is a quantity of an inventiveagent that, when administered to a human in need thereof, is sufficientto modulate and/or inhibit the activity of RIP1 kinase such that adisease condition which is mediated by that activity is reduced,alleviated or prevented. The amount of a given compound that willcorrespond to such an amount will vary depending upon factors such asthe particular compound (e.g., the potency (pIC₅₀), efficacy (EC₅₀), andthe biological half-life of the particular compound), disease conditionand its severity, the identity (e.g., age, size and weight) of thepatient in need of treatment, but can nevertheless be routinelydetermined by one skilled in the art. Likewise, the duration oftreatment and the time period of administration (time period betweendosages and the timing of the dosages, e.g., before/with/after meals) ofthe compound will vary according to the identity of the mammal in needof treatment (e.g., weight), the particular compound and its properties(e.g., pharmacokinetic properties), disease or disorder and its severityand the specific composition and method being used, but can neverthelessbe determined by one of skill in the art.

“Treating” or “treatment” is intended to mean at least the mitigation ofa disease or disorder in a patient. The methods of treatment formitigation of a disease or disorder include the use of the compounds inthis invention in any conventionally acceptable manner, for example forprevention, retardation, prophylaxis, therapy or cure of a RIP1kinase-mediated disease or disorder, as described hereinabove.

The compounds of the invention may be administered by any suitable routeof administration, including both systemic administration and topicaladministration. Systemic administration includes oral administration,parenteral administration, transdermal administration, rectaladministration, and administration by inhalation. Parenteraladministration refers to routes of administration other than enteral,transdermal, or by inhalation, and is typically by injection orinfusion. Parenteral administration includes intravenous, intramuscular,and subcutaneous injection or infusion. Inhalation refers toadministration into the patient's lungs whether inhaled through themouth or through the nasal passages. Topical administration includesapplication to the skin.

The compounds of the invention may be administered once or according toa dosing regimen wherein a number of doses are administered at varyingintervals of time for a given period of time. For example, doses may beadministered one, two, three, or four times per day. Doses may beadministered until the desired therapeutic effect is achieved orindefinitely to maintain the desired therapeutic effect. Suitable dosingregimens for a compound of the invention depend on the pharmacokineticproperties of that compound, such as absorption, distribution, andhalf-life, which can be determined by the skilled artisan. In addition,suitable dosing regimens, including the duration such regimens areadministered, for a compound of the invention depend on the disease ordisorder being treated, the severity of the disease or disorder beingtreated, the age and physical condition of the patient being treated,the medical history of the patient to be treated, the nature ofconcurrent therapy, the desired therapeutic effect, and like factorswithin the knowledge and expertise of the skilled artisan. It will befurther understood by such skilled artisans that suitable dosingregimens may require adjustment given an individual patient's responseto the dosing regimen or over time as individual patient needs change.Total daily dosages range from 1 mg to 2000 mg, preferably, total dailydosages range from 1 mg to 250 mg.

For use in therapy, the compounds of the invention will be normally, butnot necessarily, formulated into a pharmaceutical composition prior toadministration to a patient. Accordingly, the invention also is directedto pharmaceutical compositions comprising a compound of the inventionand one or more pharmaceutically acceptable excipients.

In one embodiment, there is provided a pharmaceutical compositioncomprising(S)-5-benzyl-N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4H-1,2,4-triazole-3-carboxamide(free base), and one or more pharmaceutically acceptable excipients. Inanother embodiment, there is provided a pharmaceutical compositioncomprising(S)-5-benzyl-N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4H-1,2,4-triazole-3-carboxamide,or a pharmaceutically acceptable salt thereof, and one or morepharmaceutically acceptable excipients. In another embodiment, there isprovided a pharmaceutical composition comprising crystalline(S)-5-benzyl-N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4H-1,2,4-triazole-3-carboxamide(free base) having the PXRD pattern of FIG. 7 and one or morepharmaceutically acceptable excipients. In another embodiment, there isprovided a pharmaceutical composition comprising crystalline(S)-5-benzyl-N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4H-1,2,4-triazole-3-carboxamide(free base) characterized by the diffraction data in Table 1, and one ormore pharmaceutically acceptable excipients. In one embodiment, there isprovided a pharmaceutical composition comprising(S)-5-benzyl-N-(7-chloro-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-3-yl)-4H-1,2,4-triazole-3-carboxamide(free base) and one or more pharmaceutically acceptable excipients. Inanother embodiment, there is provided a pharmaceutical compositioncomprising(S)-5-benzyl-N-(7-chloro-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-3-yl)-4H-1,2,4-triazole-3-carboxamide,or a pharmaceutically acceptable salt thereof, and one or morepharmaceutically acceptable excipients.

The pharmaceutical compositions of the invention may be prepared andpackaged in bulk form wherein an effective amount of a compound of theinvention can be extracted and then given to the patient such as withpowders, syrups, and solutions for injection. Alternatively, thepharmaceutical compositions of the invention may be prepared andpackaged in unit dosage form. For oral application, for example, one ormore tablets or capsules may be administered. A dose of thepharmaceutical composition contains at least a therapeutically effectiveamount of a compound of this invention (i.e., a compound of Formula (I),particularly a compound of any one of Formulas (I-IV), or a salt,particularly a pharmaceutically acceptable salt, thereof). When preparedin unit dosage form, the pharmaceutical compositions may contain from 1mg to 1000 mg of a compound of this invention.

As provided herein, unit dosage forms (pharmaceutical compositions)containing from 1 mg to 1000 mg of a compound of the invention may beadministered one, two, three, or four times per day, preferably one,two, or three times per day, and more preferably, one or two times perday, to effect treatment of a RIP1 kinase-mediated disease or disorder.

The pharmaceutical compositions of the invention typically contain onecompound of the invention. However, in certain embodiments, thepharmaceutical compositions of the invention contain more than onecompound of the invention. In addition, the pharmaceutical compositionsof the invention may optionally further comprise one or more additionalpharmaceutically active compounds.

As used herein, “pharmaceutically acceptable excipient” means amaterial, composition or vehicle involved in giving form or consistencyto the composition. Each excipient must be compatible with the otheringredients of the pharmaceutical composition when commingled such thatinteractions which would substantially reduce the efficacy of thecompound of the invention when administered to a patient andinteractions which would result in pharmaceutical compositions that arenot pharmaceutically acceptable are avoided. In addition, each excipientmust of course be of sufficiently high purity to render itpharmaceutically acceptable.

The compounds of the invention and the pharmaceutically acceptableexcipient or excipients will typically be formulated into a dosage formadapted for administration to the patient by the desired route ofadministration. Conventional dosage forms include those adapted for (1)oral administration such as tablets, capsules, caplets, pills, troches,powders, syrups, elixirs, suspensions, solutions, emulsions, sachets,and cachets; (2) parenteral administration such as sterile solutions,suspensions, and powders for reconstitution; (3) transdermaladministration such as transdermal patches; (4) rectal administrationsuch as suppositories; (5) inhalation such as aerosols and solutions;and (6) topical administration such as creams, ointments, lotions,solutions, pastes, sprays, foams, and gels.

Suitable pharmaceutically acceptable excipients will vary depending uponthe particular dosage form chosen. In addition, suitablepharmaceutically acceptable excipients may be chosen for a particularfunction that they may serve in the composition. For example, certainpharmaceutically acceptable excipients may be chosen for their abilityto facilitate the production of uniform dosage forms. Certainpharmaceutically acceptable excipients may be chosen for their abilityto facilitate the production of stable dosage forms. Certainpharmaceutically acceptable excipients may be chosen for their abilityto facilitate the carrying or transporting the compound or compounds ofthe invention once administered to the patient from one organ, orportion of the body, to another organ, or portion of the body. Certainpharmaceutically acceptable excipients may be chosen for their abilityto enhance patient compliance.

Suitable pharmaceutically acceptable excipients include the followingtypes of excipients: diluents, fillers, binders, disintegrants,lubricants, glidants, granulating agents, coating agents, wettingagents, solvents, co-solvents, suspending agents, emulsifiers,sweeteners, flavoring agents, flavor masking agents, coloring agents,anti-caking agents, humectants, chelating agents, plasticizers,viscosity increasing agents, antioxidants, preservatives, stabilizers,surfactants, and buffering agents. The skilled artisan will appreciatethat certain pharmaceutically acceptable excipients may serve more thanone function and may serve alternative functions depending on how muchof the excipient is present in the formulation and what otheringredients are present in the formulation.

Skilled artisans possess the knowledge and skill in the art to enablethem to select suitable pharmaceutically acceptable excipients inappropriate amounts for use in the invention. In addition, there are anumber of resources that are available to the skilled artisan whichdescribe pharmaceutically acceptable excipients and may be useful inselecting suitable pharmaceutically acceptable excipients. Examplesinclude Remington's Pharmaceutical Sciences (Mack Publishing Company),The Handbook of Pharmaceutical Additives (Gower Publishing Limited), andThe Handbook of Pharmaceutical Excipients (the American PharmaceuticalAssociation and the Pharmaceutical Press).

The pharmaceutical compositions of the invention are prepared usingtechniques and methods known to those skilled in the art. Some of themethods commonly used in the art are described in Remington'sPharmaceutical Sciences (Mack Publishing Company).

Accordingly, another embodiment of this invention is a method ofpreparing a pharmaceutical composition comprising the step of admixingcrystalline(S)-5-benzyl-N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4H-1,2,4-triazole-3-carboxamide(free base) having the PXRD pattern of FIG. 7 with one or morepharmaceutically acceptable excipients. In another embodiment, there isprovided a method of preparing a pharmaceutical composition comprisingthe step of admixing crystalline(S)-5-benzyl-N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4H-1,2,4-triazole-3-carboxamide(free base) characterized by the diffraction data in Table 1, with oneor more pharmaceutically acceptable excipients.

In one aspect, the invention is directed to a solid oral dosage formsuch as a tablet or capsule comprising an effective amount of a compoundof the invention and a diluent or filler. Suitable diluents and fillersinclude lactose, sucrose, dextrose, mannitol, sorbitol, starch (e.g.corn starch, potato starch, and pre-gelatinized starch), cellulose andits derivatives (e.g. microcrystalline cellulose), calcium sulfate, anddibasic calcium phosphate. The oral solid dosage form may furthercomprise a binder. Suitable binders include starch (e.g. corn starch,potato starch, and pre-gelatinized starch), gelatin, acacia, sodiumalginate, alginic acid, tragacanth, guar gum, povidone, and celluloseand its derivatives (e.g. microcrystalline cellulose). The oral soliddosage form may further comprise a disintegrant. Suitable disintegrantsinclude crospovidone, sodium starch glycolate, croscarmelose, alginicacid, and sodium carboxymethyl cellulose. The oral solid dosage form mayfurther comprise a lubricant. Suitable lubricants include stearic acid,magnesium stearate, calcium stearate, and talc.

EXAMPLES

The following examples illustrate the invention. These examples are notintended to limit the scope of the present invention, but rather toprovide guidance to the skilled artisan to prepare and use thecompounds, compositions, and methods of the present invention. Whileparticular embodiments of the present invention are described, theskilled artisan will appreciate that various changes and modificationscan be made without departing from the spirit and scope of theinvention.

The reactions described herein are applicable for producing compounds ofthe invention having a variety of different substituent groups (e.g.,R¹, R², etc.), as defined herein. The skilled artisan will appreciatethat if a particular substituent is not compatible with the syntheticmethods described herein, the substituent may be protected with asuitable protecting group that is stable to the reaction conditions. Theprotecting group may be removed at a suitable point in the reactionsequence to provide a desired intermediate or target compound. Suitableprotecting groups and the methods for protecting and de-protectingdifferent substituents using such suitable protecting groups are wellknown to those skilled in the art; examples of which may be found in T.Greene and P. Wuts, Protecting Groups in Chemical Synthesis (3rd ed.),John Wiley & Sons, NY (1999).

Names for the intermediate and final compounds described herein weregenerated using the software naming program ACD/Name Pro V6.02 availablefrom Advanced Chemistry Development, Inc., 110 Yonge Street, 14^(th)Floor, Toronto, Ontario, Canada, M5C 1T4 (http://www.acdlabs.com/) orthe naming program in ChemDraw, Struct=Name Pro 12.0, as part ofChemBioDraw Ultra, available from CambridgeSoft. 100 CambridgeParkDrive, Cambridge, Mass. 02140 USA (www.cambridgesoft.com).

It will be appreciated by those skilled in the art that in certaininstances these programs may name a structurally depicted compound as atautomer of that compound. It is to be understood that any reference toa named compound or a structurally depicted compound is intended toencompass all tautomers of such compounds and any mixtures of tautomersthereof.

EXAMPLES

In the following experimental descriptions, the following abbreviationsmay be used:

Abbreviation Meaning AcOH acetic acid aq aqueous BOC, tBOCtert-butoxycarbonyl brine saturated aqueous sodium chloride BuOH butanolCDCl₃ deuterated chloroform CDI 1,1′-carbonyldiimidazole CH₂Cl₂ or DCMmethylene chloride or dichloromethane CH₃CN or MeCN acetonitrile CH₃NH₂methylamine d day DAST diethylaminosulfur trifluoride DCE1,2-dichloroethane DCM 1,2-dichloromethane DIEA or DIPEA diisopropylethylamine DMA dimethylacetamide DMAP 4-Dimethylaminopyridine DMFN,N-dimethylformamide DMSO dimethylsulfoxide EDC1-ethyl-3-(3-dimethylaminopropyl) carbodiimide equiv equivalents Etethyl Et₃N or TEA triethylamine Et₂O diethyl ether EtOAc ethyl acetateFCC flash column chromatography h, hr hour(s) HATUO-(7-Azabenzotriazol-lyl)-N,N,N′,N′- tetramethylyroniumhexafluorophosphate HCl hydrochloric acid HPLC high-performance liquidchromatography ICl iodine monochloride i-Pr₂NEtN′,N′-diisopropylethylamine KOt-Bu potassium tert-butoxide KOH potassiumhydroxide LCMS liquid chromatography-mass spectroscopy LiHDMS lithiumhexamethyldisilazide LiOH lithium hydroxide Me methyl MeOH or CH₃OHmethanol MgSO₄ magnesium sulfate min minute(s) MS mass spectrum μwmicrowave NaBH₄ sodium borohydride Na₂CO₃ sodium cathonate NaHCO₃ sodiumbicarbonate NaOH sodium hydroxide Na₂SO₄ sodium sulfate NBSN-Bromosuccinimide N₂H₂ hydrazine NH₄Cl ammonium chloride NH₄OH ammoniumhydroxide NiCl₂•6H₂O nickel (II) chloride hexahydrate NMPN-methyl-2-pyrrolidone NMR nuclear magnetic resonance Pd/C palladium oncarbon Ph phenyl POCl₃ phosphoryl chloride PSI pound-force per squareinch rm or rxn mixture reaction mixture rt room temperature satd.saturated sm starting material TEA thiethylamine TFA trifluoroaceticacid THF tetrahydrofuran TMEDA tetramethylethylenediamine TMSItrimethylsilyl iodide TMSN₃ trimethylsilyl azide T3P2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphorinane- 2,4,6-trioxide t_(R)or Rf retention time

Preparation 1(S)-2-((tert-butoxycarbonyl)amino)-3-(2-nitrophenoxy)propanoic acid

To a suspension of sodium hydride (9.75 g, 244 mmol) in DMF (250 mL) wasadded a solution of(S)-2-((tert-butoxycarbonyl)amino)-3-hydroxypropanoic acid (25 g, 122mmol) in 50 mL of DMF dropwise over 10 min at 0° C. Vigorous gasevolution was observed. Once gas evolution had ceased,1-fluoro-2-nitrobenzene (12.85 mL, 122 mmol) was added dropwise neat at0° C. The reaction mixture was allowed to stir at room temperature for16 hr. The reaction mixture was partitioned between ethyl acetate (1000mL) and 0.5 M HCl solution (1000 mL). The layers were separated, theorganic layer was washed with water (3×400 ml), brine (400 mL), andconcentrated under reduced pressure to provide the crude product. Thecrude compound was purified by silica gel column using 0-10% MeOH in DCMto afford (S)-2-((tert-butoxycarbonyl)amino)-3-(2-nitrophenoxy)propanoicacid (32 g, 76 mmol, 62.3% yield) as reddish yellow semi solid. 1H NMR(400 MHz, CDCl₃) δ ppm 7.88 (dd, J=8.46, 1.64 Hz, 1H), 7.52-7.61 (m,1H), 7.06-7.15 (m, 2H), 5.68 (br. d., 1H), 4.75 (br. s., 1H), 4.60-4.72(m, 1H), 2.07 (s, 2H), 1.48 (s, 9H). MS (m/z) 325.13 (M−H⁺).

The following intermediates used for the preparation of titled examplecompounds were synthesized using methods analogous to the ones describedabove.

The following intermediates used for the preparation of titled examplecompounds were synthesized using(S)-3-amino-2-((tert-butoxycarbonyl)amino)-propanoic acid as describedby Scott B. Hoyt et. al. in patent application WO 2008/106077.

Preparation 2(S)-3-(2-aminophenoxy)-2-((tert-butoxycarbonyl)amino)propanoic acid

A solution of(S)-2-((tert-butoxycarbonyl)amino)-3-(2-nitrophenoxy)propanoic acid (32g, 98 mmol) and Pd/C (2.82 g, 2.65 mmol) in methanol (500 mL) using Parrapparatus was hydrogenated with 60 PSI at rt for 2 hr. The TLC (10% MeOHin DCM; Rf: 0.4) shows complete conversion of all of the startingmaterial and the reaction mixture was filtered through a celite bed. Thecelite bed was washed with methanol (130 mL, 3 times) and the combinedfiltrate was concentrated to afford(S)-3-(2-aminophenoxy)-2-((tert-butoxycarbonyl)amino)propanoic acid (32g, 95 mmol, 97% yield) as pale brown semi solid. The residue was used inthe next step without further purification. ¹H NMR (DMSO-d₆) δ: 7.42(br. s., 1H), 6.74 (d, J=7.1 Hz, 1H), 6.64-6.70 (m, 1H), 6.57-6.62 (m,1H), 6.47 (td, J=7.6, 1.6 Hz, 1H), 4.40 (d, J=4.3 Hz, 1H), 4.24 (dd,J=9.5, 4.9 Hz, 1H), 4.00 (dd, J=9.6, 3.5 Hz, 1H), 1.41 (s, 9H). MS (m/z)295.19 (M−H⁺), 222.15 (-tBuO group).

The following intermediates used for the preparation of titled examplecompounds were synthesized using methods analogous to the ones describedabove.

Preparation 3 (S)-tert-butyl(4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)carbamate

To a solution of(S)-3-(2-aminophenoxy)-2-((tert-butoxycarbonyl)amino)propanoic acid (23g, 78 mmol) and DIPEA (14.91 mL, 85 mmol) in DMSO (230 mL) stirred undernitrogen at 10° C. was added HATU (29.5 g, 78 mmol) portionwise during15 min. The reaction mixture was stirred at room temperature for 16 hr.Reaction was quenched with water (900 mL) (resulting in formation of asolid) and was stirred at 18° C. for 20 min. The resultant solid wasfiltered, washed with excess water (3 times) and dried in vacuo (highvacuum) to afford (S)-tert-butyl(4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)carbamate (18 g,61.6 mmol, 79% yield) as a pale brown solid. TLC: 50% EtOAc in Hexane;Rf: 0.55. 1H NMR (400 MHz, DMSO-d₆) δ ppm 9.92 (s, 1H), 6.99-7.21 (m,5H), 4.17-4.45 (m, 3H), 1.36 (s, 9H). MS (m/z): 179.16 ([M-BOC]+H⁺).

The following intermediates used for the preparation of titled examplecompounds were synthesized using methods analogous to the ones describedabove.

Preparation 4 (S)-tert-butyl(7-fluoro-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)carbamate

To a suspension of (S)-tert-butyl(7-fluoro-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)carbamate(0.89 g, 2.70 mmol) and K₂CO₃ (0.392 g, 2.84 mmol) in DMF (10.0 mL) atrt was added a solution of MeI (0.161 mL, 2.57 mmol) in DMF. Thereaction mixture was stirred at rt overnight, then additional 0.74 eq ofMeI and K₂CO₃ were added and the reaction was monitored by LCMS. Thereaction mixture was diluted with EtOAc then washed with water (2×),sat. aq. NH₄Cl and brine. The organic phase was concentrated in vacuothen purified by FCC [EtOAc/Hex: 15-50%] to yield the desired product(640 mg, 76%). ¹H NMR (DMSO-d₆) δ: 7.44 (dd, J=9.9, 3.0 Hz, 1H),7.17-7.25 (m, 2H), 7.10 (td, J=8.5, 3.0 Hz, 1H), 4.23-4.42 (m, 3H), 3.28(s, 3H), 1.35 (s, 9H). MS (m/z) 211.1 ([M-BOC]+H⁺).

The following intermediates used for the preparation of titled examplecompounds were synthesized using methods analogous to the one describedabove.

Preparation 5 (S)-tert-butyl(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)carbamate

To a solution of (S)-tert-butyl(4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)carbamate (30 g, 108mmol) and Cs₂CO₃ (49.2 g, 151 mmol) in DMF (300 mL) stirred undernitrogen at room temp was added methyl iodide (8.09 mL, 129 mmol)dropwise during 15 min. The reaction mixture was stirred at rt for 16hr. TLC (30% EtOAc in Hexane; Rf: 0.4) shows reaction was complete. Thereaction was poured into cold water (1500 mL) which formed a solid, theresultant solid was filtered, the filter cake was washed with water (twotimes) and dried in vacuo to afford the crude compound. This wastriturated with 5% Et₂O in hexane (300 mL) to afford (S)-tert-butyl(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)carbamate(19 g, 62.7 mmol, 58.1% yield) as a brown solid. ¹H NMR (DMSO-d₆) δ:7.47 (dd, J=7.7, 1.6 Hz, 1H), 7.23-7.33 (m, 2H), 7.14-7.21 (m, 2H),4.25-4.41 (m, 3H), 3.28 (s, 3H), 1.34 (s, 9H). MS (m/z) 193.33([M-BOC]+H⁺).

The following intermediates used for the preparation of titled examplecompounds were synthesized using methods analogous to the one describedabove.

Preparation 6(S)-3-amino-7-fluoro-2,3-dihydrobenzo[b][1,4]oxazepin-4(5H)-onetrifluoroacetate

To a suspension of (S)-tert-butyl(7-fluoro-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)carbamate(105.0 mg, 0.354 mmol) in DCM (1.5 mL) was added TFA (0.191 mL, 2.481mmol). The reaction became homogeneous almost immediately and wasallowed to stir at rt and monitored by LCMS. (about 2 h). The reactionwas diluted with ethyl ether then concentrated under reduced pressure(repeated 3 times) to give the desired product as a TFA salt. The samplewas once azeotroped with toluene. Quantitative recovery was assumed.

The following intermediates used for the preparation of titled examplecompounds were synthesized using methods analogous to the one describedabove.

Preparation 7 4,5-dihydro-1H-benzo[b]azepin-2(3H)-one

To a solution of 3,4-dihydronaphthalen-1(2H)-one (4.55 mL, 34.2 mmol) inmethanesulfonic acid (40 mL) cooled in an ice/brine bath was addedsodium azide (2.5 g, 38.5 mmol) in 5 portions over 15 minutes. Moderategas evolution. Mixture was stirred cooled for 15 minutes, then at rt for30 minutes. Reaction was poured over ice and stirred for 10 minutes. Theresulting solid was filtered, rinsed with water and hexanes, and driedto give 6.10 g tan solid. ¹H NMR (DMSO-d₆) δ: 9.51 (br. s., 1H),7.16-7.29 (m, 2H), 7.04-7.12 (m, 1H), 6.96 (d, J=7.6 Hz, 1H), 2.68 (t,J=6.8 Hz, 2H), 2.04-2.19 (m, 4H); MS (m/z) 162.0 (M+H⁺).

The following intermediates used for the preparation of titled examplecompounds were synthesized using methods analogous to the ones describedabove.

Preparation 8 3-iodo-4,5-dihydro-1H-benzo[b]azepin-2(3H)-one

To a mixture of 4,5-dihydro-1H-benzo[b]azepin-2(3H)-one (10.6 g, 65.8mmol) in DCM (150 mL) cooled in an ice/water bath was added TMEDA (29.8mL, 197 mmol), then dropwise over 20 minutes was added TMSI (26.9 mL,197 mmol). The mixture was stirred cooled for 60 minutes, iodine (25.03g, 99 mmol) was added and the mixture was stirred cooled for another 60minutes. The reaction was quenched with 5% Na₂S₂O₃ and stirred 15minutes. The resulting solid was filtered and dried to give 11.3 g tansolid. Layers of filtrate were separated. Organics were concentrated toa solid, triturated in diethyl ether and solid was filtered and dried togive 5.52 g light brown solid (87% yield, both batches). ¹H NMR(DMSO-d₆) δ: 9.93 (s, 1H), 7.22-7.30 (m, 2H), 7.09-7.17 (m, 1H), 6.99(d, J=7.3 Hz, 1H), 4.63 (dd, J=9.1, 6.8 Hz, 1H), 2.52-2.81 (m, 4H); MS(m/z) 288.0 (M+H⁺).

The following intermediates used for the preparation of titled examplecompounds were synthesized using methods analogous to the ones describedabove.

Preparation 9 3-amino-4,5-dihydro-1H-benzo[b]azepin-2(3H)-one

Step 1: To a solution of 3-iodo-4,5-dihydro-1H-benzo[b]azepin-2(3H)-one(16.8 g, 58.5 mmol) in N,N-Dimethylformamide (DMF) (100 mL) was addedsodium azide (4.57 g, 70.2 mmol) (mild exotherm) and mixture was stirredat rt for 1 hour. A precipitate formed after 30 minutes. Ice was addedto the reaction and it was then diluted with 300 mL water. More solidprecipitated out and the mixture was stirred for 10 minutes. Filteredtan solid, rinsed with water and used as-is in next step (was not driedbecause next step contained water). Small amount dried for HNMRanalysis. ¹H NMR (DMSO-d₆) δ: 10.05 (s, 1H), 7.20-7.33 (m, 2H),7.06-7.17 (m, 1H), 7.00 (d, J=7.8 Hz, 1H), 3.89 (dd, J=11.6, 8.1 Hz,1H), 2.65-2.81 (m, 2H), 2.41 (tt, J=12.7, 7.8 Hz, 1H), 2.04-2.17 (m,1H); MS (m/z) 203.0 (M+H⁺).

Step 2: To a solution of 3-azido-4,5-dihydro-1H-benzo[b]azepin-2(3H)-onein THF (120 mL) was added 1.0 mL water and PPh₃ resin (21.5 g, 3 mmol/gloading, 1.1 eq, 64.4 mmol, Aldrich). Stirred at rt for 20 hours.Reaction was filtered to remove resin, rinsed with THF and filtrate wasconcentrated. Triturated solid in 10% DCM/diethyl ether, filtered anddried to give a tan solid (9.13 g, 85% yield over 2 steps). ¹H NMR(DMSO-d₆) δ: 9.68 (br. s., 1H), 7.18-7.29 (m, 2H), 7.04-7.13 (m, 1H),6.96 (d, J=7.8 Hz, 1H), 3.13 (dd, J=11.4, 7.8 Hz, 1H), 2.55-2.70 (m,2H), 2.27 (tt, J=12.9, 7.7 Hz, 1H), 1.70-1.83 (m, 1H), 1.62 (br. s.,2H); MS (m/z) 177.0 (M+H⁺).

The following intermediates used for the preparation of titled examplecompounds were synthesized using methods analogous to the ones describedabove.

Preparation 10 (S)-3-amino-4,5-dihydro-1H-benzo[b]azepin-2(3H)-one

To a solution of 3-amino-4,5-dihydro-1H-benzo[b]azepin-2(3H)-one (24.1g, 127 mmol) in isopropanol (300 mL) at 70° C. was added L-pyroglutamicacid (16.42 g, 127 mmol). Stirred for 30 minutes. Added 400 mL moreisopropanol to facilitate stirring. Then 2-hydroxy-5-nitrobenzaldehyde(0.638 g, 3.82 mmol) was added and mixture was stirred at 70° C. for 3.5days. Mixture was cooled to rt, solid was filtered, rinsing withisopropanol and hexanes. Solid was dried to give a tan solid as thepyroglutamic acid salt (33 g, 84%). The % ee=97.4% @ 220 nm and 97.8% @254 nm. MS (m/z) 177.0 (M+H⁺).

(S)-3-amino-4,5-dihydro-1H-benzo[b]azepin-2(3H)-one, pyroglutamic acidsalt (33 g) was basified with minimum amount of concentrated NH₄OH andextracted with DCM four times. The combined organics were concentratedto a solid which was triturated in diethyl ether, filtered and dried togive a light orange/tan solid as free base (19.01 g, 81%). ¹H NMR(DMSO-d₆) δ: 9.70 (br. s., 1H), 7.17-7.30 (m, 2H), 7.05-7.13 (m, 1H),6.96 (d, J=7.8 Hz, 1H), 3.15 (dd, J=11.5, 8.0 Hz, 1H), 2.56-2.73 (m,2H), 2.28 (tt, J=12.9, 7.6 Hz, 1H), 2.04 (br. s., 2H), 1.69-1.83 (m,1H); MS (m/z) 177.0 (M+H⁺).

The following intermediates used for the preparation of titled examplecompounds were synthesized using methods analogous to the ones describedabove.

Preparation 11(S)-3-amino-1-methyl-4,5-dihydro-1H-benzo[b]azepin-2(3H)-one, HCl salt

Step 1: To a mixture of(S)-3-amino-4,5-dihydro-1H-benzo[b]azepin-2(3H)-one (0.615 g, 3.49 mmol)in DCM (20 mL) was added TEA (0.730 mL, 5.24 mmol) and BOC₂O (0.851 mL,3.66 mmol). The reaction was stirred at rt for 1 hour, diluted withwater and layers were separated. The organics were concentrated anddried to give 950 mg of (S)-tert-butyl(2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-3-yl)carbamate as anoff-white solid. ¹H NMR (DMSO-d₆) δ: 9.71 (s, 1H), 7.22-7.30 (m, 2H),7.08-7.15 (m, 1H), 6.95-7.03 (m, 2H), 3.87 (dt, J=12.1, 8.2 Hz, 1H),2.61-2.70 (m, 2H), 2.19 (ddd, J=12.0, 8.0, 4.0 Hz, 1H), 2.01-2.12 (m,1H), 1.34 (s, 9H); MS (m/z) 277 (M+H⁺).

Step 2: To a mixture of cesium carbonate (1.592 g, 4.89 mmol) and(S)-tert-butyl(2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-3-yl)carbamate (950 mg, 3.40mmol) in N,N-Dimethylformamide (DMF) (10 mL) was added iodomethane(0.262 mL, 4.19 mmol). The reaction was stirred at rt for 20 hours, thenwater (30 mL) was added and mixture was stirred vigorously for 15minutes. The resulting solid was filtered, rinsed with water and hexanesand dried to give 800 mg of (S)-tert-butyl(1-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-3-yl)carbamate asan off-white solid. ¹H NMR (DMSO-d₆) δ: 7.34-7.39 (m, 2H), 7.29 (d,J=7.3 Hz, 1H), 7.18-7.24 (m, 1H), 7.03 (d, J=8.6 Hz, 1H), 3.86 (dt,J=11.6, 8.3 Hz, 1H), 3.27 (s, 3H), 2.60-2.66 (m, 2H), 2.01-2.13 (m, 2H),1.33 (s, 9H); MS (m/z) 291 (M+H⁺).

Step 3: To a solution of (S)-tert-butyl(1-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-3-yl)carbamate (800mg, 2.73 mmol) in DCM (20 mL) was added HCl (4.0 M in dioxane) (4.0 mL,16.00 mmol). The mixture was stirred at rt for 1.5 hours, thenconcentrated and dried to give 670 mg of(S)-3-amino-1-methyl-4,5-dihydro-1H-benzo[b]azepin-2(3H)-one, HCl saltas a tan solid. ¹H NMR (DMSO-d₆) δ: 8.33 (br. s., 3H), 7.39-7.43 (m,2H), 7.36 (d, J=7.1 Hz, 1H), 7.24-7.30 (m, 1H), 3.62 (dd, J=11.4, 8.1Hz, 1H), 3.57 (s, 3H), 2.70-2.77 (m, 2H), 2.44 (ddd, J=12.1, 8.0, 4.2Hz, 1H), 2.07-2.17 (m, 1H); MS (m/z) 191 (M+H⁺).

The following intermediates used for the preparation of titled examplecompounds were synthesized using methods analogous to the ones describedabove.

Preparation 12 8-bromo-4,5-dihydro-1H-benzo[b]azepin-2(3H)-one

Step 1: To a solution of sodium acetate (7.47 g, 91 mmol) in Water(13.33 mL) was added hydroxylamine hydrochloride (6.33 g, 91 mmol), thenEthanol (40 mL) and 7-bromo-3,4-dihydronaphthalen-1(2H)-one (10.25 g,45.5 mmol). The white slurry was heated at 80° C. for 45 minutes.Reaction was removed from heat, stirred for 10 minutes, then poured overice and stirred until all ice melted. Filtered resulting solid, rinsedwith water and dried to give a white solid (10.58 g, 95%). ¹H NMR(DMSO-d₆) δ: 11.29 (s, 1H), 7.94 (d, J=2.0 Hz, 1H), 7.42 (dd, J=8.2, 2.1Hz, 1H), 7.17 (d, J=8.3 Hz, 1H), 2.66 (dt, J=16.9, 6.3 Hz, 4H), 1.74(quin, J=6.4 Hz, 2H); MS (m/z) 240/242 (M+H⁺), bromine splittingpattern.

Step 2: To methanesulfonic acid (100 mL) was added phosphorus pentoxide(9.70 g, 68.3 mmol) and mixture was heated at 90° C. for 1.5 hours.Removed from heat and added 7-bromo-3,4-dihydronaphthalen-1(2H)-oneoxime (10.58 g, 43.2 mmol) in portions over 10 minutes. Mixture washeated at 80° C. for 20 hours. Reaction was removed from heat and pouredover ice, then 50% w/w NaOH was added slowly along with ice to controltemperature. Resulting precipitate was stirred for 10 minutes, filtered,rinsed with water and dried to give a pink powder that was 80% pure(9.81 g, 74%). ¹H NMR (DMSO-d₆) δ: 9.61 (s, 1H), 7.19-7.32 (m, 2H), 7.13(d, J=2.0 Hz, 1H), 2.66 (t, J=6.9 Hz, 2H), 2.04-2.21 (m, 4H); MS (m/z)240/242 (M+H⁺), bromine splitting pattern.

Preparation 13(R)-2-((tert-butoxycarbonyl)amino)-3-((2-nitrophenyl)thio)propanoic acid

To a solution of (R)-2-((tert-butoxycarbonyl)amino)-3-mercaptopropanoicacid (5.02 g, 22.69 mmol) in Water (32 mL) was added NaHCO₃(5.72 g, 68.1mmol) stirred at 25° C. was slowly added a solution of1-fluoro-2-nitrobenzene (3.20 g, 22.69 mmol) in Ethanol (40 mL). Thereaction mixture was stirred at reflux for 4 h and cooled to rt. LCMSindicated the reaction was completed. The ethanol was removed undervacuum and the resulting aqueous phase was diluted with water (50 ml),washed with ether (2×100 ml), (discarded the ether phase LCMS showedminor product). The aqueous was acidified to pH 4 with 1N aqueous HCland extracted with DCM (2×300 mL). The organic layers were combined,washed with brine, dried over Na₂SO₄ and concentrated in vacuo to affordthe title compound as yellow solid(R)-2-((tert-butoxycarbonyl)amino)-3-((2-nitrophenyl)thio)propanoic acid(7 g, 20.4 mmol, 90% yield). MS (m/z) 343 (M+H⁺).

Preparation 14(R)-3-((2-aminophenyl)thio)-2-((tert-butoxycarbonyl)amino)propanoic acid

To a solution of(R)-2-((tert-butoxycarbonyl)amino)-3-((2-nitrophenyl)thio)propanoic acid(0.8 g, 2.337 mmol) in MeOH (100 mL) was added ammonium chloride (0.250g, 4.67 mmol) and zinc (1.528 g, 23.37 mmol) at 25° C. After stirring atrt for 1 h, the mixture was heated to 75 C for 2 h. The resultingmixture was then directly filtered through celite and celite was washedwith boiling MeOH (2×100 ml). The combined organic were partiallyconcentrated under vacuum (25 ml) and the residue was allowed to standovernight at rt. Solid salts were eliminated by filtration, then DCM(100 ml) and water (100 ml) was added to the filtrate, the resultingorganic phase was washed with water (3×100 ml), dried over Na₂SO₄ andconcentrated in vacuo to afford the title compound as solid(R)-3-((2-aminophenyl)thio)-2-((tert-butoxycarbonyl)amino)propanoic acid(700 mg, 2.241 mmol, 96% yield). MS (m/z) 313 (M+H⁺).

Preparation 15 (R)-tert-butyl(4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepin-3-yl)carbamate

To a solution of(R)-3-((2-aminophenyl)thio)-2-((tert-butoxycarbonyl)amino)propanoic acid(3.3 g, 10.56 mmol) in DCM (100 mL) was addedN1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diaminehydrochloride (2.228 g, 11.62 mmol). Stirred at rt for 5 min, then added4-methylmorpholine (1.742 mL, 15.85 mmol). The reaction mixture wasstirred at 25° C. for 5 h. LCMS showed product and the reaction wascompleted. Removed all the DCM and added 200 ml of EtOAc and the mixturewas washed with water, 0.1N HCl(aq), NaHCO_(3(aq)) and brine. Theorganic phase was dried over Na₂SO₄ and concentrated under reducedpressure to afford crude product. ISCO purification (eluting with 0-70%of EtOAc in hexane) to afford the pure title compound as (R)-tert-butyl(4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepin-3-yl)carbamate (1.5 g,5.10 mmol, 48.2% yield). 1H NMR (400 MHz, CDCl₃) δ=7.73-7.57 (m, 1H),7.39 (td, J=1.4, 7.6 Hz, 2H), 7.27-7.03 (m, 2H), 5.58 (br. s., 1H), 4.49(dt, J=7.2, 11.8 Hz, 1H), 3.85 (dd, J=6.7, 11.0 Hz, 1H), 2.95 (t, J=11.4Hz, 1H), 1.42 (s, 9H). MS (m/z) 295 (M+H⁺).

Preparation 16 (R)-3-amino-2,3-dihydrobenzo[b][1,4]thiazepin-4(5H)-one,Hydrochloride

To a solution of (R)-tert-butyl(4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepin-3-yl)carbamate (100 mg,0.340 mmol) in dioxane (3 mL) was added HCl (0.425 mL, 1.699 mmol, 4M indioxane). The reaction mixture was stirred at 25° C. for 18 h. LCMSindicated the product w/o starting material. Removed all the solventsand washed the solid with ether and the solid was used without furtherpurification. MS (m/z) 195 (M+H⁺).

The following intermediates used for the preparation of titled examplecompounds was synthesized using methods analogous to the ones describedabove.

Preparation 17 (R)-tert-butyl(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepin-3-yl)carbamate

To a solution of (R)-tert-butyl(4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepin-3-yl)carbamate (200 mg,0.679 mmol) in N,N-Dimethylformamide (DMF) (5 mL) was added Cs₂CO₃ (332mg, 1.019 mmol) The reaction mixture was stirred at rt for 5 min, thenMeI (0.051 mL, 0.815 mmol) was added. The reaction mixture was stirredat rt for 3 h and LCMS showed the reaction was completed. Added EtOAcand washed with water, brine and dried over Na₂SO₄. Removed all thesolvent to afford the title compound as (R)-tert-butyl(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepin-3-yl)carbamate(200 mg, 0.649 mmol, 95% yield). MS (m/z) 309 (M+H⁺).

Preparation 18(R)-3-amino-5-methyl-2,3-dihydrobenzo[b][1,4]thiazepin-4(5H)-onehydrochloride

To a solution of (R)-tert-butyl(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepin-3-yl)carbamate(290 mg, 0.940 mmol) in DCM (3 mL) was added HCl (7.05 mL, 28.2 mmol, 4Min dioxane). The reaction mixture was stirred at 25° C. for 3 h. LCMSindicated the product w/o starting material. Removed all the solventsand the solid (200 mg, 87%) was washed with ether and hexane and usedwithout further purification. MS (m/z) 209 (M+H⁺).

Preparation 19(S)-3-((tert-butoxycarbonyl)amino)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-7-carboxylicacid

To a solution of ester (500.0 mg, 1.427 mmol) in THF (16 mL)/Water (5mL) was added LiOH (2.141 mL, 2.141 mmol) as a solution in water (1.0mL). After 3 h, the reaction mixture was poured into cold water (70 mL)then extracted twice with EtOAc. The aqueous phase was acidified to pH-3then extracted with EtOAc twice to extract the desired product. Theorganic phase was dried over Na₂SO₄, filtered, then concentrated invacuo. The solid was azeotroped twice with toluene then concentrated toa final solid that was sufficiently pure to use in the next step. Nofurther purification appeared necessary. Yield: 456 mg (90%) whitesolid. MS (m/z) 337.3 (M+H⁺).

Preparation 20 (S)-tert-butyl(7-(hydrazinecarbonyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]xazepin-3-yl) carbamate

To a suspension of(S)-3-((tert-butoxycarbonyl)amino)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-7-carboxylicacid (228 mg, 0.678 mmol) in dry DCM (5.5 ml) was added CDI (115 mg,0.712 mmol) as a solid. The reaction mixture was stirred at rt for 1 h30 min then this mixture was added slowly dropwise to a separatestirring solution of anhydrous hydrazine (217 mg, 6.78 mmol) in 3.0 mLof dry DCM at rt. After 1 h, the reaction mixture was diluted with DCMthen washed with water and brine. After drying the sample over Na₂SO₄and concentration, the solid product had sufficient purity to carry tothe next step, (164 mg, 69%). ¹H NMR (DMSO-d₆) δ: 9.84 (s, 1H), 7.88 (d,J=2.0 Hz, 1H), 7.71 (dd, J=8.3, 2.0 Hz, 1H), 7.26 (d, J=8.3 Hz, 1H),7.21 (d, J=7.8 Hz, 1H), 4.55 (br. s., 1H), 4.30-4.41 (m, 4H), 3.31 (s,3H), 1.34 (s, 9H). MS (m/z) 351.3 (M+H⁺).

Preparation 21 (S)-tert-butyl(5-methyl-4-oxo-7-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)carbamate

To a solution of (S)-tert-butyl(7-(hydrazinecarbonyl)-5-methyl-4-oxo-2,3,4,5-tetrahydro benzo[b][1,4]xazepin-3-yl)carbamate (191.0 mg, 0.545 mmol) in N,N-Dimethylformamide(DMF) (3.0 mL) was added TEA (0.114 mL, 0.818 mmol) followed by CDI (97mg, 0.600 mmol). The mixture was stirred at rt. The reaction mixture wasdiluted with EtOAc then washed with cold dilute HCl, water (2×), andbrine. The organic phase was dried over Na₂SO₄, filtered, thenconcentrated in vacuo. The residue was washed with small amount of DCMthen filtered and collected as a white powder then used in the next stepwithout further purification (150.0 mg, 80%). ¹H NMR (DMSO-d₆) δ: 12.67(br. s., 1H), 7.83 (d, J=2.0 Hz, 1H), 7.68 (dd, J=8.3, 2.0 Hz, 1H), 7.35(d, J=8.3 Hz, 1H), 7.23 (d, J=7.8 Hz, 1H), 4.32-4.45 (m, 3H), 1.35 (s,9H). MS (m/z) 377.3 (M+H⁺).

Preparation 22(S)-3-amino-5-methyl-7-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)-2,3-dihydrobenzo[b][1,4]oxazepin-4(5H)-one,Hydrochloride

To a solution of (S)-tert-butyl(5-methyl-4-oxo-7-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)carbamate(40.0 mg, 0.106 mmol) in DCM (1.0 mL) was added a solution of 4M HCl in1,4 dioxane (0.531 mL, 2.126 mmol). The mixture was stirred at rt for 1h. The reaction mixture was concentrated in vacuo, then it wasazeotroped twice with toluene to yield the desired product. MS (m/z)277.1 (M+H⁺).

Preparation 23(S)-3-(5-benzylisoxazole-3-carboxamido)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-7-carboxylic acid

To a solution of (S)-methyl3-(5-benzylisoxazole-3-carboxamido)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-7-carboxylate(332 mg, 0.762 mmol) in THF (6 mL)/Water (2.0 mL) was added LiOH (1.144mL, 1.144 mmol) as a solution in water. Reaction was stirred at rt forabout 2 h. The reaction mixture was diluted with water then extractedwith EtOAc twice. The aqueous phase was acidified to pH-3.0 then it wasextracted with EtOAc. The latter organic phase was dried over Na₂SO₄then filtered and concentrated in vacuo to yield the desired product asa solid. The solid was warmed in toluene then decanted to give the finalsolid product that was used directly in the next step. ¹H NMR (DMSO-d₆)δ: 13.18 (br. s., 1H), 8.87 (d, J=8.1 Hz, 1H), 7.98 (d, J=2.0 Hz, 1H),7.85 (dd, J=8.3, 2.0 Hz, 1H), 7.25-7.38 (m, 6H), 6.55 (s, 1H), 4.87 (dt,J=11.8, 7.7 Hz, 1H), 4.64 (dd, J=11.6, 10.1 Hz, 1H), 4.46 (dd, J=9.9,7.6 Hz, 1H), 4.22 (s, 2H). MS (m/z) 422.3 (M+H⁺).

Preparation 24(S)-5-benzyl-N-(7-(hydrazinecarbonyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)isoxazole-3-carboxamide

To a suspension of(S)-3-(5-benzylisoxazole-3-carboxamido)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-7-carboxylic acid (178.0 mg, 0.422 mmol) in DCM(6.0 mL) was added CDI (75 mg, 0.465 mmol). The reaction mixture wasstirred at rt for 1 h 30 min. The mixture was then added slowly dropwiseto a solution of hydrazine (0.199 mL, 6.34 mmol) in 0.50 mL DCM. After 1h LCMS indicated about 79% conversion to the desired product. Thereaction mixture was diluted with DCM then washed with water and brine.After drying the sample over Na₂SO₄ and concentration, the solid producthad sufficient purity to carry to next step. ¹H NMR (DMSO-d₆) δ: 9.86(s, 1H), 8.90 (d, J=8.1 Hz, 1H), 7.91 (d, J=2.3 Hz, 1H), 7.73 (dd,J=8.3, 2.0 Hz, 1H), 7.27-7.38 (m, 6H), 6.55 (s, 1H), 4.85 (dt, J=11.8,7.9 Hz, 1H), 4.62 (dd, J=11.6, 10.1 Hz, 1H), 4.54 (br. s., 2H), 4.44(dd, J=9.9, 7.8 Hz, 1H), 4.22 (s, 2H), 3.33 (s, 3H). MS (m/z) 436.2(M+H⁺).

Preparation 25(S)-5-benzyl-N-(7-(hydrazinecarbonyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-pyrazole-3-carboxamide

To a solution of (S)-methyl3-(5-benzyl-1H-pyrazole-3-carboxamido)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-7-carboxylate(191.0 mg, 0.440 mmol) in MeOH (5.0 mL) was added hydrazine monohydrate(0.058 mL, 1.199 mmol) as a solution in MeOH (1.0 mL). The reactionmixture was refluxed overnight then it was diluted with EtOAc andpartitioned with water. The organic phase was dried over Na₂SO₄,filtered, then concentrated in vacuo. The residue was purified by FCC(MeOH-DCM: 0-7.0%]) to yield the desired the product (119.0 mg, 62.3%).¹H NMR (DMSO-d₆) δ: 13.22 (s, 1H), 9.85 (s, 1H), 8.09 (d, J=8.1 Hz, 1H),7.90 (d, J=2.0 Hz, 1H), 7.73 (dd, J=8.3, 2.0 Hz, 1H), 7.18-7.34 (m, 6H),6.37 (d, J=1.5 Hz, 1H), 4.84 (dt, J=11.6, 7.8 Hz, 1H), 4.48-4.62 (m,3H), 4.36-4.47 (m, 1H), 3.99 (s, 2H). MS (m/z) 435.2 (M+H⁺).

Preparation 26 (S)-tert-butyl(7-((2-cyanoethyl)carbamoyl)-5-methyl-4-oxo-2,3,4,5-tetra hydrobenzo[b][1,4]oxazepin-3-yl)carbamate

To a suspension of(S)-3-((tert-butoxycarbonyl)amino)-5-methyl-4-oxo-2,3,4,5-tetra-hydrobenzo[b][1,4]oxazepine-7-carboxylicacid (185.0 mg, 0.550 mmol) in DCM (5.0 mL) was added1-chloro-N,N,2-trimethylprop-1-en-1-amine (88 mg, 0.660 mmol) as asolution in DCM (0.10 ml) dropwise over 1 min. The reaction mixture wasstirred at rt for 1 h and became a homogeneous solution. The reactionmixture was cooled in an ice-bath then 3-aminopropanenitrile (154 mg,2.200 mmol) was added dropwise as a solution in DCM (0.25 mL). After 10min, the ice-bath was removed then 10% aq citric acid solution was addedand the mixture was stirred vigorously for 15 min. The organic phase wasseparated, washed with sat. aq sodium bicarbonate, brine then dried overNa₂SO₄ and concentrated in vacuo. The residue was purified by FCC[EtOAc-Hex: 45-80%] to yield the desired product (190.0 mg, 89%). MS(m/z) 389.3 (M+H⁺).

Preparation 27 (S)-tert-butyl(7-(1-(2-cyanoethyl)-1H-tetrazol-5-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)carbamate

To a solution of (S)-tert-butyl(7-((2-cyanoethyl)carbamoyl)-5-methyl-4-oxo-2,3,4,5-tetra hydrobenzo[b][1,4]oxazepin-3-yl)carbamate (188.0 mg, 0.484 mmol) and pyridine(0.243 mL, 3.00 mmol) in DCM (2.0 mL) was added phosphorus pentachloride(161 mg, 0.774 mmol). The reaction mixture was heated to reflux for 3.0h. The reaction mixture was cooled to rt then TMSN₃ (0.257 mL, 1.936mmol) was added and the reaction mixture was stirred overnight. At 20 h,5.0 eq of TMS-N3 followed by 3.0 eq pyridine was added. The reactionmixture was warmed in an oil bath at 45 deg C. for -4 h. The reactionmixture was carefully quenched with a few drops of sat. aq. NaHCO₃initially, then after 5 min excess NaHCO₃ was added and the mixture wasstirred for 15 min. The organic phase was separated and washed with 10%aq citric acid and brine. The organic solution was dried over Na₂SO₄,filtered and concentrated in vacuo. The residue was purified by FCC(EtOAc-Hex: 50-70%) to yield the desired product (152.0 mg, 72%). ¹H NMR(DMSO-d6) δ: 7.87 (d, J=2.0 Hz, 1H), 7.68 (dd, J=8.2, 2.1 Hz, 1H), 7.44(d, J=8.3 Hz, 1H), 7.21 (d, J=8.6 Hz, 1H), 4.73-4.87 (m, 2H), 4.35-4.54(m, 3H), 3.24 (t, J=6.3 Hz, 2H), 1.36 (s, 9H). MS (m/z) 414.3 (M+H⁺).

Preparation 28(S)-3-(5-(3-amino-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-7-yl)-1H-tetrazol-1-yl)propanenitrile,Trifluoroacetic acid salt

To a solution of (S)-tert-butyl(7-(1-(2-cyanoethyl)-1H-tetrazol-5-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)carbamate(152 mg, 0.368 mmol) in DCM (1.0 mL) was added TFA (0.50 mL, 6.49 mmol).The mixture was stirred at rt for 1 h then the reaction mixture wasconcentrated in vacuo to a residue that was azeotroped with toluene toyield solid product that was used directly in the next step (149.0 mg,95%). MS (m/z) 314.2 (M+H⁺).

Preparation 29(S)-3-(5-benzylisoxazole-3-carboxamido)-N-(2-cyanoethyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-7-carboxamide

To a suspension of(S)-3-(5-benzylisoxazole-3-carboxamido)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-7-carboxylicacid (87.0 mg, 0.206 mmol) in DCM (2.0 mL) was added1-chloro-N,N,2-trimethylprop-1-en-1-amine (33.1 mg, 0.248 mmol) as asolution in DCM (0.10 ml) dropwise over 1 min. The reaction mixture wasstirred at rt for 1 h and became a homogeneous solution. The reactionmixture was cooled in an ice-bath then 3-aminopropanenitrile (57.9 mg,0.826 mmol) was added dropwise as a solution in DCM (0.25 mL). Theice-bath was removed then 10% aq citric acid solution was added and themixture was stirred vigorously for 15 min. The organic phase wasseparated, washed with sat. aq sodium bicarbonate and brine then driedover sodium sulfate and concentrated in vacuo. The residue was purifiedby FCC(EtOAc-Hex: 60-80%) to yield the desired product(67.0 mg, 68.5%).MS (m/z) 474.4 (M+H⁺).

Preparation 30 (S)-tert-butyl(5-methyl-7-(N,N-dimethylcarbamoyl)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)carbamate

To a solution of(S)-3-((tert-butoxycarbonyl)amino)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-7-carboxylicacid (100.0 mg, 0.297 mmol DMSO (2.0 mL) was added DIEA (0.109 mL, 0.624mmol) then HATU (113 mg, 0.297 mmol). After 5 min dimethylamine (0.156mL, 0.312 mmol was added and the reaction mixture was stirred at rt. Thereaction mixture was diluted with EtOAc then washed with sat. aq. NH₄Cl,water and brine. The organic phase was dried over Na₂SO₄, filtered andconcentrated in vacuo, The residue was purified by FCC [EtOAc-Hex:15-50%] to yield the desired product (44.0 mg, 40.7%). ¹H NMR (DMSO-d₆)δ: 7.53 (d, J=1.8 Hz, 1H), 7.27-7.31 (m, 1H), 7.21-7.25 (m, 1H), 7.18(d, J=8.1 Hz, 1H), 4.27-4.44 (m, 3H), 3.29 (s, 3H), 2.99 (br. s., 6H),1.35 (s, 9H). MS (m/z) 364.0 (M+H⁺).

The following intermediates used for the preparation of titled examplecompounds were synthesized using methods analogous to the ones describedabove.

Preparation 31(S)-3-amino-N,N,5-trimethyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-7-carboxamidetrifluoroacetate

To a suspension of (S)-tert-butyl(5-methyl-7-(N,N-dimethylcarbamoyl)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)carbamate(46.0 mg, 0.113 mmol) in DCM (1.5 mL) was added TFA (0.175 mL, 2.269mmol). The reaction mixture was stirred for 4 h at rt and found to becomplete by LC/MS. The reaction mixture was concentrated in vacuo thenazeotroped with toluene twice. The residue was used without furtherpurification and used directly in the next step. MS (m/z) 264.0 (M+H⁺).

The following intermediates used for the preparation of titled examplecompounds were synthesized using methods analogous to the ones describedabove.

Preparation 32 (S)-di-tert-butyl(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3,7-diyl)dicarbamate

A mixture of(S)-3-((tert-butoxycarbonyl)amino)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-7-carboxylic acid (78.0 mg, 0.232 mmol),diphenylphosphorylazide (DPPA) (0.070 mL, 0.325 mmol), TEA (0.091 mL,0.649 mmol), and tBuOH (0.439 mL, 4.59 mmol) in toluene were firstheated to 70 deg C. for 30 min then to 100 deg C. for overnight. After20 min some desired product was observed; the reaction mixture was leftovernight and appeared to be complete. The solvent was removed in vacuothen the residue was purified by FCC [E/H 25%]. (No work-up was neededand the sample was well purified by column.); ¹H NMR (DMSO-d₆) δ: 9.47(br. s., 1H), 7.54 (d, J=1.5 Hz, 1H), 7.25 (dd, J=8.5, 1.9 Hz, 1H), 7.15(d, J=8.8 Hz, 1H), 7.07 (d, J=8.6 Hz, 1H), 4.30-4.39 (m, 1H), 4.20-4.26(m, 2H), 3.23 (s, 3H), 1.48 (s, 9H), 1.35 (s, 9H). MS (m/z) 408.3(M+H⁺).

Preparation 33(S)-3,7-diamino-5-methyl-2,3-dihydrobenzo[b][1,4]oxazepin-4(5H)-one

To a suspension of (S)-di-tert-butyl(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3,7-diyl)dicarbamate(75.0 mg, 0.184 mmol) in DCM (1.5 mL) was added HCl (0.782 mL, 3.13mmol). The reaction mixture was stirred overnight at rt. The solvent wasevaporated, then the residue was azeotroped with toluene to obtain asolid residue that was used in the next step without furtherpurification; quantitative yield was assumed. MS (m/z) 208.1 (M+H⁺).

Preparation 34(S)—N-(7-amino-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-5-benzylisoxazole-3-carboxamide

A solution of 5-benzylisoxazole-3-carboxylic acid (37.4 mg, 0.184 mmol)and HATU (77 mg, 0.202 mmol) in acetonitrile (2.5 mL) (1 mL) was stirredfor 1 h. This mixture was added slowly to a second mixture of mixture of(9.0 eq)N-methylmorpholine (0.182 mL, 1.656 mmol) and(S)-3,7-diamino-5-methyl-2,3-dihydrobenzo[b][1,4]oxazepin-4(5H)-one, 2hydrochloride (51.5 mg, 0.184 mmol). LCMS showed predominantly oneproduct 70% plus bis-coupled 23%. The reaction mixture was diluted withEtOAc then washed with water and brine. After drying over sodiumsulfate, and filtering the sample was concentrated in vacuo and purifiedby FCC [EtOAc-Hex: 20-60%]. ¹H NMR (DMSO-d₆) δ: 8.78 (d, J=8.3 Hz, 1H),7.27-7.39 (m, 5H), 6.87 (d, J=8.3 Hz, 1H), 6.58 (d, J=2.8 Hz, 1H), 6.55(s, 1H), 6.43 (dd, J=8.6, 2.5 Hz, 1H), 5.16 (s, 2H), 4.77-4.87 (m, 1H),4.36-4.44 (m, 1H), 4.20-4.27 (m, 3H), 3.22 (s, 3H). MS (m/z) 393.2(M+H⁺).

Preparation 35 (S)-tert-butyl(3-((tert-butoxycarbonyl)amino)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-7-yl)(methyl)carbamate

To a suspension of (S)-di-tert-butyl(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3,7-diyl)dicarbamate(60.0 mg, 0.147 mmol) DMF (1.0 mL) was added Cs₂CO₃ (48.0 mg, 0.147mmol) then MeI (9.21 μL, 0.147 mmol). The reaction mixture was combinedwith a second batch reaction of 40 mg scale and both were processedtogether. The reaction mixture was diluted with EtOAc then washedsuccessively with water and brine. The organic phase was dried overNa₂SO₄ and filtered. The concentrated residue was purified by FCC(EtOAc-Hex: 15-35%) to yield an 86.0 mg mixture of desired product withsome starting material (7:3 by LC/MS) that was used in the next step. MS(m/z) 422.4 (M+H⁺).

Preparation 36(S)-3-amino-5-methyl-7-(methyl-amino)-2,3-dihydrobenzo[b][1,4]oxazepin-4(5H)-one

To a mixture of (S)-tert-butyl(3-((tert-butoxycarbonyl)amino)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-7-yl)(methyl)carbamatefrom previous step (86.0 mg, 0.204 mmol) in DCM (3.0 ml) was added HCl(1.020 mL, 4.08 mmol) as a 4 M HCl solution in 1,4 dioxane. The reactionmixture was stirred at rt overnight then additional 0.5 mL of 4M HCl in1,4 dioxane was added and stirring was continued 1 h. The reactionmixture was concentrated in vacuo, then azeotroped with toluene to yieldresidual solid having the desired product that was used directly in thenext step. MS (m/z) 222.1 (M+H⁺).

Preparation 37(S)-3-((5-Amino-6-chloropyrimidin-4-yl)amino)-2-((tert-butoxycarbonyl)amino)propanoicacid

To a suspension of 4,6-dichloropyrimidin-5-amine (0.402 g, 2.448 mmol)and triethylamine (0.751 mL, 5.39 mmol) in BuOH (10 mL) was added(S)-3-amino-2-((tert-butoxycarbonyl)amino)propanoic acid (0.5 g, 2.448mmol) at rt. The reaction mixture was heated at 90° C. After heating for1 hr, another 10 mL of BuOH and EtOH (15 mL) were added to the reactionmixture. After heating for 2 days (Note: still some starting materialremained), the reaction mixture was concentrated, then diluted withwater and EtOAc. After separation, the aqueous solution was extractedwith EtOAc (×2), and then the aqueous solution was acidified with 1N HCl(pH around 3). After extraction with EtOAc (×3), the combined organicsolution was washed with brine, dried over MgSO4. After filtration andevaporation in vacuo,(S)-3-((5-amino-6-chloropyrimidin-4-yl)amino)-2-((tert-butoxycarbonyl)amino)propanoicacid (430 mg, 1.296 mmol, 52.9% yield) was obtained as pale brownishsolids, which was used for the next reaction without furtherpurification. MS (m/z) 332.2 (M+H⁺). ¹H NMR (DMSO-d₆) δ: 12.67 (br. s.,1H), 7.75 (s, 1H), 7.09 (d, J=8.3 Hz, 1H), 6.85-6.91 (m, 1H), 5.05 (s,2H), 4.24 (td, J=8.0, 5.3 Hz, 1H), 3.71-3.82 (m, 1H), 3.55-3.68 (m, 1H),1.35-1.41 (m, 9H).

The following intermediates used for the preparation of titled examplecompounds were synthesized using a method analogous to the onesdescribed above using 4,6-dichloro-2-methylpyrimidin-5-amine and2-chloro-5-fluoro-3-nitropyridine in DMSO as solvent at 70° C.

Preparation 38 (S)-tert-butyl(4-chloro-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-7-yl)carbamate

To a solution of(S)-3-((5-amino-6-chloropyrimidin-4-yl)amino)-2-((tert-butoxycarbonyl)amino)propanoicacid (300 mg, 0.904 mmol) and HATU (378 mg, 0.995 mmol) in DMSO (4.0 mL)was added DIEA (0.237 mL, 1.356 mmol) at rt. After 5 hr at rt, another378 mg of HATU and 0.24 mL of DIEA were added. After stirring forovernight at rt, water was added, then extracted with EtOAc (×3). Thecombined organic solution was washed with brine, and dried over MgSO₄.After filtration and evaporation in vacuo, the crude material waspurified by silica gel column chromatography (Biotage, 25 g cartridge,10% to 60% EtOAc in hexane) to give (S)-tert-butyl(4-chloro-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-7-yl)carbamate(125 mg, 0.394 mmol, 43.6% yield) as colorless solid. MS (m/z) 314.2(M+H⁺). ¹H NMR (DMSO-d₆) δ: 9.49 (s, 1H), 8.14-8.22 (m, 1H), 8.07 (s,1H), 6.95 (d, J=7.1 Hz, 1H), 4.23-4.34 (m, 1H), 3.41-3.51 (m, 2H), 1.39(s, 9H).

Preparation 39 (S)-tert-butyl(6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-7-yl)carbamate

To a suspension of (S)-tert-butyl(4-chloro-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-7-yl)carbamate(300 mg, 0.956 mmol) in EtOH (5 mL), EtOAc (5.00 mL), and MeOH (7.5 mL)was added Pd/C (153 mg, 0.143 mmol) at rt. The reaction mixture wasstirred under H2 balloon for 3 hr. The reaction mixture was filtered andwashed with EtOAc and MeOH. The combined filtrate was evaporated invacuo and the resultant solid (S)-tert-butyl(6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-7-yl)carbamate(260 mg, 0.912 mmol, 95% yield) was used for the next reaction withoutfurther purification. MS (m/z) 280.2 (M+H⁺). ¹H NMR (DMSO-d₆) δ: 10.32(s, 1H), 9.41 (br. s., 1H), 8.50 (s, 1H), 8.01 (s, 1H), 7.06 (d, J=7.1Hz, 1H), 4.36-4.50 (m, 1H), 3.53-3.63 (m, 1H), 3.40-3.52 (m, 1H), 1.40(s, 9H).

The following intermediate used for the preparation of titled examplecompounds was synthesized from (S)-tert-butyl(4-chloro-2,5-dimethyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-7-yl)carbamateusing methods analogous to the ones described above.

Preparation 40 (S)-tert-butyl(4-chloro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-7-yl)carbamate

To a solution of (S)-tert-butyl(4-chloro-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-7-yl)carbamate(0.7 g, 2.231 mmol) in DMF (10 ml) was added NaH (0.094 g, 2.343 mmol)at rt. After 30 min at rt, iodomethane (0.146 ml, 2.343 mmol) was addedand stirred for 1 hr 20 min. The addition of water triggered aprecipitation. The solid was filtered and washed with water and hexane.The wet solid was collected and dried at 50° C. in a vacuum oven to give(S)-tert-butyl(4-chloro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-7-yl)carbamate(620 mg, 1.797 mmol, 81% yield) as a colorless solid, which was used forthe next reaction without further purification. MS (m/z) 328.2 (M+H⁺).¹H NMR (DMSO-d₆) δ: 8.18 (s, 1H), 8.09 (br. d, 1H), 7.02 (d, J=7.6 Hz,1H), 4.38-4.48 (m, 1H), 3.37-3.54 (m, 2H), 3.12 (s, 3H), 1.38 (s, 9H).

The following intermediates used for the preparation of titled examplecompounds were synthesized using methods analogous to the ones describedabove.

Preparation 41 (S)-tert-butyl(7-bromo-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-3-yl)carbamate

To a mixture of(S)-3-amino-7-bromo-4,5-dihydro-1H-benzo[b]azepin-2(3H)-one (800 mg,3.14 mmol) in DCM (20 mL) was added NEt3 (0.656 mL, 4.70 mmol) and BOC₂O(0.764 mL, 3.29 mmol). The mixture was stirred at rt for 1 h, and thenwas diluted with H₂O (20 mL). The organic layer was separated andconcentrated. The resulting residue was purified by Isco Combiflash(20%-80% EtOAc/Hexane; 40 g RediSep column). Collected fractionscontaining the product were combined and concentrated to give thedesired product as a white solid (900 mg, 81% yield). ¹H NMR (CDCl₃) δppm 9.21 (s, 1H), 7.32 (d, J=2.0 Hz, 1H), 7.24 (dd, J=8.3, 2.0 Hz, 1H),6.83 (d, J=8.3 Hz, 4H), 5.68 (d, J=7.8 Hz, 1H), 4.17-4.31 (m, 1H),2.76-2.95 (m, 1H), 2.52-2.68 (m, 2H), 1.94-2.01 (m, 1H), 1.39 (s, 9H);MS (m/z): 355 (M+H⁺).

Preparation 42 Tert-butyl(7-cyano-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-3-yl)carbamate

Tert-butyl(7-bromo-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-3-yl)carbamate (200mg, 0.563 mmol), zinc cyanide (99 mg, 0.845 mmol), Pd₂dba₃ (258 mg,0.282 mmol), and S-Phos (277 mg, 0.676 mmol) were mixed in a 5 mlmicrowave vial. The vial was flushed with N₂ 3 times, and then 2 ml ofDMF was added. The reaction mixture was microwaved using an EmrysOptimizer (150 W, absorption normal, 120° C., 20 min). The mixture wasthen filtered and the filtrate was concentrated. The residue waspurified by Isco Combiflash (20%-50% EtOAc/Hexane; 40 g RediSep column).Collected fractions containing the product were combined andconcentrated to give the desired product as a brown oil. This oil waslyophilized to a pale yellow solid (146 mg, 86% yield). ¹H NMR (CDCl₃) δ□ppm 9.18 (s, 1H), 7.47-7.59 (m, 2H), 7.13 (d, J=8.1 Hz, 1H), 5.50 (d,J=7.8 Hz, 1H), 4.26 (dt, J=11.4, 7.7 Hz, 1H), 2.84-3.00 (m, 1H),2.62-2.79 (m, 2H), 1.98-2.12 (m, 1H), 1.41 (s, 9H); MS (m/z): 302(M+H⁺).

Preparation 433-amino-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepine-7-carbonitrile

To a mixture of tert-butyl(7-cyano-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-3-yl)carbamate (70mg, 0.234 mmol) in DCM (5 mL) was added HCl (4N in dioxane) (0.31 mL,1.23 mmol). The reaction mixture was stirred at rt for 1 h. The mixturewas then concentrated and dried. This crude material was taken to thenext step without purification (47 mg, 100% yield). MS (m/z): 202(M+H⁺).

Preparation 44 (S)-tert-butyl(2-oxo-7-(1H-tetrazol-5-yl)-2,3,4,5-tetrahydro-1H-benzo[b]azepin-3-yl)carbamate

(S)-tert-butyl(7-cyano-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-3-yl)carbamate (100mg, 0.332 mmol) was dissolved in DMF (2 mL), and then sodium azide (64.9mg, 0.999 mmol) and ammonium chloride (53.8 mg, 1.006 mmol) were added.The mixture was maintained at 120° C. for 16 h. The mixture was filteredand the filtrate was then concentrated and the residue was purified byIsco Combiflash (2%-10% MeOH/CH₂Cl₂, 10% NEt3 in MeOH; 12 g RediSepcolumn). Collected fractions containing the product were combined andconcentrated to give the desired product as a colorless oil (114 mg,100% yield). MS (m/z): 345 (M+H⁺).

Preparation 45(S)-3-amino-7-(1H-tetrazol-5-yl)-4,5-dihydro-1H-benzo[b]azepin-2(3H)-one

(S)-tert-butyl(2-oxo-7-(1H-tetrazol-5-yl)-2,3,4,5-tetrahydro-1H-benzo[b]azepin-3-yl)carbamate(114 mg, 0.332 mmol) was dissolved in DCM (2 mL), and then HCl (4 N indioxane, 0.83 mL) was added. The mixture was maintained at rt for 2 h.The r×n mixture was concentrated to an off-white solid. MS (m/z): 245(M+H⁺).

Preparation 46 tert-butyl(7-bromo-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-3-yl)carbamate

To a mixture of 3-amino-7-bromo-4,5-dihydro-1H-benzo[b]azepin-2(3H)-one(1.7 g, 6.66 mmol) in DCM (50 mL) was added NEt3 (1.393 mL, 10.00 mmol)and BOC₂O (1.625 mL, 7.00 mmol). The mixture was maintained at rt for 1h. The reaction mixture was then diluted with water and the organiclayer was separated, concentrated and dried under high vacuum for 16 h.This crude material was taken to the next step without furtherpurification (2.36 g, 100% yield). MS (m/z): 355 (M+H⁺).

Preparation 47 tert-butyl(7-bromo-1-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-3-yl)carbamate

To a mixture of cesium carbonate (3.04 g, 9.33 mmol) and tert-butyl(7-bromo-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-3-yl)carbamate (2.36g, 6.66 mmol) in lml DMF and THF (50 mL) mixed solution was addediodomethane (0.500 mL, 8.00 mmol). The reaction mixture was maintainedat rt for 20 h. The mixture was then filtered and the filtrate wasconcentrated. The residue was purified by Isco Combiflash (10%-50%EtOAc/Hexane; 330 g RediSep column). Collected fractions containing theproduct were combined and concentrated to give the desired product as awhite solid (1.6 g, 65% yield). ¹H NMR (CDCl₃) δ ppm 7.44 (dd, J=8.5,2.1 Hz, 1H), 7.37 (d, J=2.3 Hz, 1H), 7.07 (d, J=8.6 Hz, 1H), 5.47 (d,J=7.6 Hz, 1H), 4.23 (dt, J=11.5, 7.5 Hz, 1H), 3.39 (s, 3H), 2.73-2.91(m, 1H), 2.49-2.65 (m, 2H), 1.87-2.03 (m, 1H), 1.42 (s, 9H); MS (m/z):369 (M+H⁺).

Preparation 48 1,1-dimethylethyl(1-methyl-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-3-yl)carbamate-dl

Tert-butyl(7-bromo-1-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-3-yl)carbamate(80 mg, 0.217 mmol) was dissolved in 50 ml THF and then cooled to −78°C. N-butyllithium (2.5M in Hexane) (0.217 mL, 0.542 mmol) was addeddropwise at −78° C. The reaction mixture was maintained at −78° C. for30 min, and then was quenched by MeOD. The mixture was washed bysat.NaHCO₃(aq). The organic layer was separated and purified by IscoCombiflash (20%-80% EtOAc/Hexane; 12 g RediSep column). Collectedfractions containing the product were combined and concentrated to givethe desired product as a white solid (64 mg, 100% yield). ¹H NMR (400MHz, CDCl₃) δ ppm 1.41 (s, 9H) 1.95 (dd, J=7.45, 3.92 Hz, 1H) 2.51-2.68(m, 2H) 2.73-2.98 (m, 1H) 3.41 (s, 3H) 4.19-4.34 (m, 1H) 5.37-5.64 (m,1H) 7.11-7.24 (m, 2H) 7.23-7.38 (m, 1H); MS (m/z): 292 (M+H⁺).

Preparation 493-amino-1-methyl-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one-di

1,1-dimethylethyl(1-methyl-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-3-yl)carbamate-dl (64mg) was dissolved in 2 mL DCM, and then 0.54 mL HCl (4N in dioxane) wasadded dropwise. The reaction mixture was maintained at rt for 4 h. Themixture was then concentrated and the crude material was taken to thenext step without further purification (35 mg, 84% yield). MS (m/z): 192(M+H⁺).

Preparation 503-amino-1-methyl-7-(2,2,2-trifluoro-1,1-dihydroxyethyl)-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one

Tert-butyl(7-bromo-1-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-3-yl)carbamate(100 mg, 0.271 mmol) was dissolved in 50 ml THF and then cooled to −78°C. N-butyllithium (2.5M in Hexane, 0.271 mL, 0.677 mmol) was addeddropwise at −78° C. This mixture was maintained at −78° C. for 30 min,and then ethyl 2,2,2-trifluoroacetate (0.129 mL, 1.083 mmol) was addeddropwise at −78° C. The mixture turned into colorless solution afteraddition. This mixture was maintained at −78° C. for 1 h, and then wasslowly warmed up to rt. The r×n mixture was quenched by MeOH, and thenwashed by sat.NH₄Cl(aq). The organic layer was separated andconcentrated. The residue was purified by Isco CombiFlash (20%-80%EtOAc/Hexane; 40 g RediSep column). Collected fractions containing theproduct were combined and concentrated to give the desired product as ayellow oil (24 mg, 23% yield). MS (m/z): 404 (M+H⁺).

1,1-Dimethylethyl[1-methyl-2-oxo-7-(2,2,2-trifluoro-1,1-dihydroxyethyl)-2,3,4,5-tetrahydro-1H-1-benzazepin-3-yl]carbamate(125 mg, 0.324 mmol) was dissolved in DCM (2 mL), and then HCl (4N indioxane) (0.809 mL, 3.24 mmol) was added. The yellow solution wasmaintained at room temperature for 16 hours. This solution was thenconcentrated to give the3-amino-1-methyl-7-(2,2,2-trifluoro-1,1-dihydroxyethyl)-1,3,4,5-tetrahydro-2H-1-benzazepin-2-oneas a yellow oil (92 mg, 100% yield). MS (m/z): 304 (M+H⁺).

Preparation 51 (S)-tert-butyl(2-oxo-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3,4,5-tetrahydro-1H-benzo[b]azepin-3-yl)carbamate

(S)-tert-butyl(7-bromo-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-3-yl)carbamate (200mg, 0.563 mmol), bis(pinacolato)diboron (157 mg, 0.619 mmol),PdCl2(dppf)-CH₂C₁₂ adduct (46.0 mg, 0.056 mmol) and potassium acetate(182 mg, 1.858 mmol) were mixed in 1,4-Dioxane (2 mL). The reactionmixture was put in an Emrys Optimizer (150 W, absorption normal, 120°C., 10 min). The reaction mixture was then partitioned between H₂O andDCM. The organic layer was washed by brine, dried over MgSO₄ andconcentrated to a brown residue. This residue was purified by IscoCombiflash (10%-80% EtOAc/Hexane; 40 g RediSep column). Collectedfractions containing the product were combined and concentrated to givethe desired product as a white solid (82 mg, 36% yield). MS (m/z): 402(M+H⁺).

Preparation 52(S)-3-amino-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4,5-dihydro-1H-benzo[b]azepin-2(3H)-one

(S)-tert-butyl(2-oxo-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3,4,5-tetrahydro-1H-benzo[b]azepin-3-yl)carbamate(82 mg, 0.205 mmol) was dissolved in 2 mL DCM, and then HCl (4N indioxane, 1.408 mL, 5.63 mmol) was added dropwise. The reaction solutionwas maintained at rt for 16 h. The solution was then concentrated to ayellow oil (62 mg, 100% yield). MS (m/z): 302 (M+H⁺).

Preparation 53(S)-5-benzyl-N-(2-oxo-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3,4,5-tetrahydro-1H-benzo[b]azepin-3-yl)-4H-1,2,4-triazole-3-carboxamide

To a magnetically stirred solution of5-benzyl-4H-1,2,4-triazole-3-carboxylic acid (41.7 mg, 0.205 mmol) in 5mL DCM at rt was added 4-methylmorpholine (66.4 mg, 0.657 mmol) and HATU(94 mg, 0.246 mmol). A solution of(S)-3-amino-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4,5-dihydro-1H-benzo[b]azepin-2(3H)-one(62 mg, 0.205 mmol) and in 2 mL DCM was add to this mixture. Thereaction mixture was maintained at rt for 16 h. The crude mixture wasthen purified by Isco Combiflash (20%-50% EtOAc/Hexane; 40 g RediSepcolumn). Collected fractions containing the product were combined andconcentrated to give the desired product as a yellow solid (65 mg, 65%yield). MS (m/z): 488 (M+H⁺).

Preparation 54(S)-3-amino-8-hydroxy-2,3-dihydrobenzo[b][1,4]oxazepin-4(5H)-one

(S)-tert-butyl(8-methoxy-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)carbamate(300 mg, 0.973 mmol) was dissolved in DCM (15 mL) and cooled in anice/brine bath. Then boron tribromide (2.92 mL, 2.92 mmol) was added andreaction was stirred cooled for 10 minutes. Removed ice bath and stirredat rt for 60 minutes. Added another 2.0 mL BBr₃ and stirred for 45minutes, then added another 2 mL BBr₃ and stirred for another 20minutes. Reaction was cooled in an ice bath, quenched with 5 mL satd.NaHCO₃ and stirred vigorously for 5 minutes. The pH of the aqueous was˜7-8. The layers were separated and aqueous was extracted with 10%MeOH/DCM: both organics contained impurities and aqueous containedmajority product. Concentrated aqueous to give 2.4 g crude solid(contained inorganic salts). Used as is in next step. MS (m/z) 195.0(M+H⁺).

Preparation 55(S)-3-amino-5-methyl-7-(1H-pyrazol-3-yl)-2,3-dihydrobenzo[b][1,4]oxazepin-4(5H)-one

(S)-3-amino-7-bromo-5-methyl-2,3-dihydrobenzo[b][1,4]oxazepin-4(5H)-one(50.5 mg, 0.186 mmol), (1H-pyrazol-3-yl)boronic acid (31.3 mg, 0.279mmol), sodium carbonate (59.2 mg, 0.559 mmol) and Pd(PPh₃)₄ (21.53 mg,0.019 mmol) were combined in DME (2 mL) and Water (0.7 mL) and reactionwas heated at 85° C. in oil bath for 3 hours. After 2 hours, morePd(PPh₃)₄ (15 mg) and boronic acid (15 mg) were added. After 3 hours inoil bath, reaction was put in microwave at 120° C. for 15 min. Reactionwas partitioned between 10% MeOH/DCM and water. Concentrated organicsand purified by Biotage (4 g silica column; 0.5-5% MeOH/DCM (plusNH₄OH), 15 min.) to give 30 mg light yellow oil in 60% yield. ¹H NMR(DMSO-d₆) δ: 7.79 (m, 2H), 7.66 (m, 1H), 7.19 (m, 1H), 6.76 (m, 1H),4.27 (m, 1H), 4.00 (m, 1H), 3.65 (m, 1H), 3.35 (s, 3H), 1.72 (br. s.,2H); MS (m/z) 259.1 (M+H⁺).

Preparation 56(S)-3-amino-5-methyl-7-(1H-pyrazol-1-yl)-2,3-dihydrobenzo[b][1,4]oxazepin-4(5H)-one

(S)-3-amino-7-bromo-5-methyl-2,3-dihydrobenzo[b][1,4]oxazepin-4(5H)-one(100 mg, 0.369 mmol), 1H-pyrazole (50.2 mg, 0.738 mmol) and potassiumcarbonate (153 mg, 1.107 mmol) were added to 1,4-Dioxane (2.0 mL) andmixture was degassed for 10 minutes under nitrogen. Then copper(I)iodide (35.1 mg, 0.184 mmol) and N1,N2-dimethylethane-1,2-diamine (0.020mL, 0.184 mmol) were added and mixture was heated at 100° C. for 3 days.Cooled to rt, diluted with water and 10% MeOH/DCM and separated layers.Concentrated organics and purified by Biotage (12 g silica column;0.5-3% MeOH/DCM (plus NH₄OH), 15 min.; 3-4.5%, 3 min; 4.5% 5 min.) togive 18 mg light brown solid in 19% yield. ¹H NMR (DMSO-d₆) δ: 8.54 (d,J=2.5 Hz, 1H), 7.85 (d, J=2.5 Hz, 1H), 7.76 (d, J=1.5 Hz, 1H), 7.69 (dd,J=8.7, 2.7 Hz, 1H), 7.27 (d, J=8.8 Hz, 1H), 6.54-6.59 (m, 1H), 4.29 (dd,J=9.9, 7.6 Hz, 1H), 4.02 (t, J=10.7 Hz, 1H), 3.68 (br. s., 1H), 3.36 (s,3H), 1.75 (br. s., 2H); MS (m/z) 259.1 (M+H⁺).

Preparation 57 (S)-tert-butyl(2-oxo-8-(2-(pyrrolidin-1-yl)ethoxy)-2,3,4,5-tetrahydro-1H-benzo[b]azepin-3-yl)carbamate

Polymer bound PPh₃ (3 mmol/g loading, 2.5 eq, 330 mg), (S)-tert-butyl(8-hydroxy-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-3-yl)carbamate(130 mg, 0.400 mmol) and 2-(pyrrolidin-1-yl)ethanol (0.094 mL, 0.800mmol) were combined in THF (4 mL). Next added di-tert-butylazodicarboxylate (184 mg, 0.800 mmol) and stirred mixture at rt for 3days. Added 0.5 eq more of the following reagents: polymer bound PPh₃,di-tert-butyl azodicarboxylate and 2-(pyrrolidin-1-yl)ethanol andstirred for another 24 hours. Reaction was filtered through a small plugof Celite, rinsing with 10% MeOH/DCM. Filtrate was concentrated,partitioned between DCM and 6N NaOH and layers were separated. Crude wasconcentrated and purified by Biotage (4 g silica column; 1-5% MeOH/DCM(plus NH₄OH), 15 min.) to give 74 mg white foam in 46% yield. ¹H NMR(DMSO-d₆) δ: 9.64 (s, 1H), 7.15 (d, J=8.3 Hz, 1H), 6.97 (d, J=8.3 Hz,1H), 6.70 (dd, J=8.3, 2.5 Hz, 1H), 6.57 (d, J=2.5 Hz, 1H), 3.96-4.10 (m,2H), 3.88 (dt, J=11.9, 8.3 Hz, 1H), 2.77 (t, J=5.9 Hz, 2H), 2.54-2.62(m, 2H), 2.53 (m, 1H), 2.09-2.22 (m, 2H), 1.95-2.07 (m, 2H), 1.62-1.71(m, 5H), 1.34 (s, 9H); MS (m/z) 390.3 (M+H⁺).

Preparation 58 Butyl 4-butoxypicolinate

To a mixture of 4-chloropicolinic acid (1 g, 6.35 mmol) and butan-1-ol(5.80 ml, 63.5 mmol) was added sulfuric acid (0.101 ml, 1.904 mmol) andheated to 80° C. for 2 days. After cooling down to rt, the reactionmixture was diluted with water and neutralized with 1N NaOH solution topH 5-6, then extracted with EtOAc (×3). After drying over MgSO₄,filtration, and evaporation in vacuo, the residue was purified byBiotage (50 g cartridge, 0% to 40% EtOAc in hexane) to give butyl4-butoxypicolinate (765 mg, 3.04 mmol, 48.0% yield). MS (m/z) 252.1(M+H⁺). ¹H NMR (CDCl₃) δ: 8.55 (d, J=6.1 Hz, 1H), 7.65 (d, J=2.3 Hz,1H), 6.95 (dd, J=5.7, 2.7 Hz, 1H), 4.42 (t, J=6.8 Hz, 2H), 4.09 (t,J=6.4 Hz, 2H), 1.77-1.87 (m, 4H), 1.43-1.57 (m, 4H), 0.97-1.03 (m, 6H).

The following intermediates used for the preparation of titled examplecompounds were synthesized using methods analogous to the ones describedabove.

Preparation 59 Ethyl2-amino-2-(2-(2-(3-fluorophenyl)acetyl)hydrazono)acetate

2-(3-Fluorophenyl)acetohydrazide (2.90 g, 17.22 mmol) and ethyl2-ethoxy-2-iminoacetate (2.5 g, 17.22 mmol) in ethanol (30 mL) wasstirred under nitrogen at rt for overnight, the resultant suspension wasfiltered. The white solid was washed with EtOH and dried under vacuum togive the title compound ethyl2-amino-2-(2-(2-(3-fluorophenyl)acetyl)hydrazono)acetate (3 g, 11.23mmol, 65.2% yield) which was used without further purification. MS (m/z)268 (M+H⁺).

The following intermediates used for the preparation of titled examplecompounds were synthesized using methods analogous to the ones describedabove.

Preparation 60 Ethyl 5-(3-fluorobenzyl)-4H-1,2,4-triazole-3-carboxylate

Ethyl 2-amino-2-(2-(2-(3-fluorophenyl)acetyl)hydrazono)acetate (3 g,11.23 mmol) in a flask was placed in a pre-heated oil bath at 200° C.for 15 minutes. The melt was allowed to cool, the resultant solid takenup into MeOH (20 mL), and then the solvent was evaporated. The resultantwhite solid was suspended in ether (30 mF), stirred for 10 minutes,filtered off, washed with ether (40 mL), and dried under vacuum to givethe title compound ethyl5-(3-fluorobenzyl)-4H-1,2,4-triazole-3-carboxylate (1.2 g, 4.81 mmol,42.9% yield), which was used without further purification. MS (m/z) 250(M+H*).

The following intermediates used for the preparation of titled examplecompounds were synthesized using methods analogous to the ones describedabove.

Preparation 61 5-Benzyl-4H-1,2,4-triazole-3-carboxylic acid

To a solution of ethyl 5-benzyl-4H-1,2,4-triazole-3-carboxylate (8.29 g,35.85 mmol) in THF (100 mL) was added a solution of lithium hydroxide(2.00 g, 84 mmol) in water (20 mL). The mixture was stirred for 20 hoursat room temperature. The reaction was concentrated to remove THF andconc. HCl was added until pH ˜2 at which point a solid precipitated out.The suspension was stirred for 15 minutes in an ice/water bath,filtered, rinsed with cold water and dried under vacuum to give 6.93 g(80% yield) of 5-benzyl-4H-1,2,4-triazole-3-carboxylic acidhydrochloride. MS (m/z) 204 (M+H⁺).

The following intermediates used for the preparation of titled examplecompounds were synthesized using methods analogous to the ones describedabove.

Preparation 62 ethyl 1-(3-fluorobenzyl)-1H-imidazole-4-carboxylate

To a solution of ethyl 1H-imidazole-4-carboxylate (1 g, 7.14 mmol),Cs₂CO₃ (2.56 g, 7.85 mmol) and in N,N-Dimethylformamide (DMF) (5 mL) was1-(bromomethyl)-3-fluorobenzene (1.349 g, 7.14 mmol). The reactionmixture was stirred at for 5 h. LCMS showed the reaction was completedwith product. Added 150 ml of EtOAc and extracted with water, brine anddried over Na₂SO₄. Evaporated all the solvents to afford the crudeproduct as ethyl 1-(3-fluorobenzyl)-1H-imidazole-4-carboxylate (1.7 g,6.85 mmol, 96% yield). MS (m/z) 250 (M+H⁺).

The following intermediates used for the preparation of titled examplecompounds were synthesized using methods analogous to the ones describedabove.

Preparation 63 1-(3-fluorobenzyl)-1H-imidazole-4-carboxylic acid

Freshly prepared lithium hydroxide (34.2 mL, 68.5 mmol) was added to astirring, room temperature solution of ethyl1-(3-fluorobenzyl)-1H-imidazole-4-carboxylate (1.7 g, 6.85 mmol) in THF(25 mL) under N₂. The reaction was then stirred at rt overnight and LCMSshowed completed. The reaction was concentrated and then dissolved inH₂O (10 mL). 2N HCl was added dropwise until the pH=3. The white solidthat precipitated from the reaction was filtered off and washed withcold H₂O. The solid was dried under vacuum overnight to obtain titleproduct. 1-(3-fluorobenzyl)-1H-imidazole-4-carboxylic acid (1.2 g,79.5%). MS (m/z) 221 (M+H⁺).

The following intermediates used for the preparation of titled examplecompounds were synthesized using methods analogous to the ones describedabove.

Preparation 64 Ethyl 5-(4-fluorophenyl)-2,4-dioxopentanoate

To a solution of 1-(4-fluorophenyl)propan-2-one (25 g, 164 mmol) diethyloxalate (28.8 g, 197 mmol) in toluene (300 mL) stirred under nitrogen at0° C. was added potassium tert-butoxide (23.97 g, 214 mmol) in toluene(300 mL). The reaction mixture was stirred at OC for 2 more hours andthen at rt for over night. LCMS indicated the reaction was completed.Removed all the toluene and dissolved the residue in water andneutralized to pH=6 and extracted with EtOAc twice. The organic phasewas combined and washed with brine, and dried over Na₂SO₄. Removed allthe solvents to afford the title compound used without furtherpurification (32 g, 77%). MS (m/z) 253 (M+H⁺).

The following intermediates used for the preparation of titled examplecompounds were synthesized using methods analogous to the ones describedabove.

Preparation 65 Ethyl 5-(4-fluorobenzyl)-1H-pyrazole-3-carboxylate

Hydrazine (1.095 mL, 34.9 mmol) was added to a stirring room temperaturesolution of ethyl 5-(4-fluorophenyl)-2,4-dioxopentanoate (8 g, 31.7mmol) in ethanol (100 mL) under N₂. The reaction was then heated toreflux (95 C oil bath) until judged complete by HPLC (3 h). The reactionwas concentrated and purified by silica gel chromatography (solidloading, Isco, 0-45% of EtOAc in hexane). Only pure fractions werecombined and concentrated to obtain product as ethyl5-(4-fluorobenzyl)-1H-pyrazole-3-carboxylate (4 g, 16.11 mmol, 50.8%yield). MS (m/z) 249 (M+H⁺).

The following intermediates used for the preparation of titled examplecompounds were synthesized using methods analogous to the ones describedabove.

Preparation 66 5-(4-fluorobenzyl)-1H-pyrazole-3-carboxylic acid

Freshly prepared 2M LiOH aqueous solution (64.5 mL, 129 mmol) was addedto a stirring, room temperature solution of ethyl5-(4-fluorobenzyl)-1H-pyrazole-3-carboxylate (4 g, 16.11 mmol) in THF(65 mL) under N₂. The reaction was then stirred at rt for 12 hours andLCMS showed 70% completed. Heated to 50 C for 2 h and reaction wascompleted. The reaction was concentrated and then dissolved in 20 mLH₂O. To a stirring aqueous solution, 2N HCl was added dropwise until thepH=4. The white solid that precipitated from the reaction was filteredoff and washed with cold H₂O. The solid was dried under vacuum overnight(at 40° C.) to obtain title product as5-(4-fluorobenzyl)-1H-pyrazole-3-carboxylic acid (3 g, 85%). MS (m/z)221 (M+H⁺). ¹H NMR (DMSO-d₆) δ: 12.59-13.70 (m, 1H), 7.01-7.41 (m, 4H),6.46 (s, 1H), 3.95 (s, 2H).

The following intermediates used for the preparation of titled examplecompounds were synthesized using methods analogous to the ones describedabove.

Preparation 67 Ethyl5-methyl-1-(4-methylbenzyl)-1H-pyrazole-3-carboxylate

To a solution of ethyl 3-methyl-1H-pyrazole-5-carboxylate (607 mg, 3.94mmol) in THF (20 mL) was added KOH (221 mg, 3.94 mmol). After stirringfor 1 hr at rt, the reaction mixture turned to the suspension, then1-(bromomethyl)-4-methylbenzene (729 mg, 3.94 mmol) was added and heatedto reflux. After overnight, the reaction mixture was cooled down to rtand concentrated. The residue was subjected to Biotage (cartridge 50g/pre-wet 5% EtOAc/Hex/eluent: 5% to 25% EtOAc, then maintained 25%EtOAc/Hex) to give ethyl5-methyl-1-(4-methylbenzyl)-1H-pyrazole-3-carboxylate (833 mg, 3.16mmol, 80% yield) as a desired product and the regioisomer ethyl3-methyl-1-(4-methylbenzyl)-1H-pyrazole-5-carboxylate (58 mg, 0.220mmol, 5.59% yield). Ethyl5-methyl-1-(4-methylbenzyl)-1H-pyrazole-3-carboxylate: ¹H NMR (CDCl₃) δ:7.13 (d, J=7.1 Hz, 2H), 7.03 (d, 2H), 6.62 (br. s., 1H), 5.36 (br. s.,2H), 4.42 (dd, J=7.1, 1.3 Hz, 2H), 2.34 (br. s., 3H), 2.19 (s, 3H),1.35-1.50 (m, 3H); MS (m/z) 259.1 (M+H⁺). The regioisomer ethyl3-methyl-1-(4-methylbenzyl)-1H-pyrazole-5-carboxylate: ¹H NMR (CDCl₃) d:7.05-7.24 (m, 4H), 6.66 (br. s., 1H), 5.67 (br. s., 2H), 4.19-4.42 (m,2H), 2.32 (d, J=3.0 Hz, 6H), 1.27-1.40 (m, 3H).

The following intermediates used for the preparation of titled examplecompounds were synthesized using methods analogous to the ones describedabove.

Preparation 68 5-Methyl-1-(4-methylbenzyl)-1H-pyrazole-3-carboxylic acid

To a solution of ethyl5-methyl-1-(4-methylbenzyl)-1H-pyrazole-3-carboxylate (830 mg, 3.21mmol) in THF (3.0 mL) and water (3.0 mL) was added lithium hydroxide,H₂O (539 mg, 12.85 mmol) at rt. After stirring for overnight at rt, thereaction mixture was concentrated in vacuo. The aqueous solution wasdiluted with water (5 mL) and acidified with 1N HCl (about 5.1 mL) to pH3-4. The resultant white solid was collected and dried under a vacuumoven to give 5-methyl-1-(4-methylbenzyl)-1H-pyrazole-3-carboxylic acid(670 mg, 2.88 mmol, 90% yield) as white solids. MS (m/z) 231.1 (M+H⁺).¹H NMR (DMSO-d₆) δ: 12.58 (br. s., 1H), 7.16 (d, J=7.8 Hz, 2H), 7.03 (d,J=7.8 Hz, 2H), 6.51 (s, 1H), 5.32 (s, 2H), 2.27 (s, 3H), 2.22 (s, 3H).

The following intermediates used for the preparation of titled examplecompounds were synthesized using methods analogous to the ones describedabove.

Preparation 69 Ethyl 2-benzyl-2H-tetrazole-5-carboxylate

To a solution of ethyl 2H-tetrazole-5-carboxylate, sodium salt (800 mg,4.85 mmol) in DMF (8 mL) was added (bromomethyl)benzene (1.151 mL, 9.69mmol) at rt. After stirring for 48 hr at rt, Et₃N (1.013 mL, 7.27 mmol)was added to the reaction mixture, then stirred for overnight. Afteradding water, the reaction mixture was extracted with EtOAc. Thecombined organic solution was washed with water and brine, dried overMgSO₄. After filtration and concentration, the residue was subjected toBiotage (50 g of silica gel cartridge; eluent: 5% to 15% EtOAc, thenmaintained 15% EtOAc/Hex) to give ethyl2-benzyl-2H-tetrazole-5-carboxylate (342 mg, 1.473 mmol, 30.4% yield,unoptimized) as a major product: MS (m/z) 233.1 (M+H⁺); ¹H NMR (DMSO-d₆)δ: 7.36-7.46 (m, 5H), 6.05 (s, 2H), 4.40 (q, J=7.1 Hz, 2H), 1.33 (t,3H). The regioisomer ethyl 1-benzyl-1H-tetrazole-5-carboxylate (87 mg,0.375 mmol, 7.73% yield) was obtained as a minor product: ¹H NMR(DMSO-d₆) δ: 7.29-7.43 (m, 5H), 5.92 (s, 2H), 4.44 (q, J=7.1 Hz, 2H),1.33 (t, 3H) (Note: some mixture of both products was also obtained).

The following intermediate used for the preparation of titled examplecompounds was synthesized using methods analogous to the ones describedabove.

Preparation 70 2-Benzyl-2H-tetrazole-5-carboxylic acid

To a solution of ethyl 2-benzyl-2H-tetrazole-5-carboxylate (338 mg,1.455 mmol) in THF (3 mL) and water (3.00 mL) was added LiOH (183 mg,4.37 mmol). After stirring for 1 hr at rt, the reaction mixture wasconcentrated in vacuo and the residual aqueous solution was acidifiedwith 1N HCl (around pH ˜2-3). A small amount of white solids wasprecipitated out. After collecting solids, the aqueous solution wasplaced in a hood and allowed to slow evaporation of water. Another whitesolid was obtained (followed this step two more times. Note: someproduct was still detected in water). The combined solid was dried in avacuum oven at 50° C. to give 2-benzyl-2H-tetrazole-5-carboxylic acid(167.4 mg, 0.820 mmol, 56.3% yield) as white solids. MS (m/z) 205.0(M+H⁺). ¹H NMR (DMSO-d₆) δ: 14.30 (br. s., 1H), 7.33-7.49 (m, 5H), 6.03(s, 2H).

The following intermediates used for the preparation of titled examplecompounds were synthesized using methods analogous to the ones describedabove.

Preparation 71 Ethyl 5-(difluoro(phenyl)methyl)isoxazole-3-carboxylate

Ethyl 5-benzoylisoxazole-3-carboxylate (630 mg, 2.57 mmol) was dissolvedin 2 mL of dichloroethane (DCE), and then a solution of DAST (0.944 mL,7.71 mmol) in 2 mL of DCE was added dropwise at 0° C. The reactionmixture was maintained at 50° C. for 16 h, and then the mixture wasconcentrated. The resulting brown residue was purified by IscoCombiflash (10%-30% EtOAc/Hexane; 80 g Isco RediSep column). Collectedfractions containing the product were combined and concentrated to givethe desired product as a yellow oil (207 mg, 31% yield). ¹H NMR (CDCl₃)δ ppm 7.56-7.64 (m, 2H), 7.45-7.56 (m, 3H), 6.87 (s, 1H), 4.45 (q, J=7.2Hz, 4H), 1.41 (t, J=7.1 Hz, 3H); MS (m/z): 268 (M+H⁺).

Preparation 72 5-(difluoro(phenyl)methyl)isoxazole-3-carboxylic acid

Ethyl 5-(difluoro(phenyl)methyl)isoxazole-3-carboxylate (207 mg, 0.775mmol) was dissolved in 2 mL of THF, and then lithium hydroxidemonohydrate (48.8 mg, 1.162 mmol) was added. The reaction mixture wasmaintained at rt for 16 h. The r×n mixture was neutralized by adding asolution of 4N HCl/dioxane dropwise. The mixture was then filtered andthe filtrate was concentrated to a yellow oil (185 mg, 100% yield). MS(m/z): 240 (M+H⁺).

Preparation 73 5-(hydroxy(phenyl)methyl)isoxazole-3-carboxylic acid

Ethyl 5-benzoylisoxazole-3-carboxylate (400 mg, 1.631 mmol) wasdissolved in 5 mL MeOH, and then NaBH4 (93 mg, 2.447 mmol) was added at0° C. The reaction mixture was maintained at rt for 16 h. The mixturewas concentrated, and then partitioned between sat. NaHCO₃(aq) and DCM.The organic layer was concentrated and dissolved in 1 mL THF. An aqueoussolution of LiOH (1.2 mL, 50 mg/ml solution) was added to this THFsolution. The mixture was maintained at rt for 16 h. A solution of HCl(0.8 mL, 4N in dioxane) was added to the mixture. The organic layer wasseparated and concentrated to a yellow oil (190 mg, 53% yield). ¹H NMR(DMSO-d₆) δ ppm 7.26-7.54 (m, 6H), 6.50 (s, 2H), 5.91 (s, 1H); MS (m/z):220 (M+H⁺).

Preparation 74 Ethyl 5-benzylisoxazole-3-carboxylate

A solution of the ethyl 2-chloro-2-(hydroxyimino)acetate (39.1 g, 258mmol) was dispensed into a solution of prop-2-yn-1-ylbenzene (10 g, 86mmol) and triethylamine (29.4 mL, 430 mmol) in CH₃CN (300 mL). Afterstanding for overnight at 80° C. the solvent was removed in vacuum. Thecrude was dissolved in EtOAc (200 mL) and was washed with saturatedsodium bicarbonate solution (50 mL), water (50 mL) and saturated brine(50 mL). The organic phase was separated and dried over sodium sulphateand evaporated in vacuo to give ethyl 5-benzylisoxazole-3-carboxylate (6g, 25.9 mmol, 30% yield) as a yellow solid. Used directly in the nextstep without further purification. MS (m/z): 232 (M+H⁺).

Preparation 75 5-Benzylisoxazole-3-carboxylic acid

A solution of the ethyl 5-benzylisoxazole-3-carboxylate (6 g, 25.9 mmol)was 5 dispensed into a solution of the sodium hydroxide (2.1 mL, 78mmol) in methanol (100 mL) and water (10 mL). After standing for 2 h at20° C., the solvent was removed in vacuum. The residue was acidifiedwith dilute HCl (20 mL) and then extracted with EtOAc (50 mL). Theorganic phase was washed with water (20 mL) and saturated brine (20 mL),and dried over sodium sulphate. Evaporation in vacuo gave5-benzylisoxazole-3-carboxylic acid (3.2 g, 15.31 mmol, 59.0% yield) asayellow solid. ¹H NMR (DMSO-d₆) δ ppm 14.0 (bs, 1H), 7.2-7.4 (m, 5H),6.6 (s, 1H), 4.2 (s, 2H); MS (m/z): 204 (M+H⁺).

Preparation 76(S)-3-amino-5-methyl-2,3-dihydrobenzo[b][1,4]oxazepin-4(5H)-onehydrochloride

To a solution of (S)-tert-butyl(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)carbamate(28 g, 96 mmol)) in DCM (300 mL) was added 4M HCl (71.8 mL, 287 mmol)and reaction stirred under nitrogen at room temp for 3 hr. The solventswere evaporated to dryness to yield the crude compound which wastriturated with diethyl ether (200 mL), filtered and dried in vacuo toafford (S)-3-amino-5-methyl-2,3-dihydrobenzo[b][1,4]oxazepin-4(5H)-onehydrochloride (22.2 g, 97 mmol, 101% yield) as brown solid. MS (m/z):193.20 (M+H⁺).

The following intermediates used for the preparation of titled examplecompounds were synthesized using methods analogous to the ones describedabove.

Preparation 77 5-(4-Chlorobenzyl)isoxazole-3-carboxylic acid

To a solution of 1-(4-chlorophenyl)propan-2-one (10 g, 59.3 mmol) in THF(150 mL) in an ice bath was added NaH (1.423 g, 59.3 mmol) portion wiseover 30 min. Dimethyl oxalate (7.0 g, 59.3 mmol) was added at roomtemperature for 1 hour and the mixture was stirred at 25° C. for 2hours. The solvent was removed in vacuo and the residue was dissolved inEtOAc which was washed with water. The aqueous phase was separated andextracted with EtOAc. The combined organic phases were dried overNa₂SO₄, filtered, and concentrated in vacuo to give methyl5-(4-chlorophenyl)-2,4-dioxopentanoate (15 g, 50.1 mmol, 84% yield) asan oil which was used in next step without further purification. MS(m/z): 255/257 (M+H⁺).

To a solution of methyl 5-(4-chlorophenyl)-2,4-dioxopentanoate (5 g,19.63 mmol) in ethanol (80 mL) was added hydroxylamine hydrochloride(1.364 g, 19.63 mmol) and then the mixture was stirred at 78° C. for 2hours monitored. The solvent was removed in vacuo and the residue wasdissolved in EtOAc which was washed with water. The aqueous phase wasseparated and extracted with EtOAc. The combined organic phases weredried over Na₂SO₄, filtered, and concentrated in vacuo to give methyl5-(4-chlorobenzyl)isoxazole-3-carboxylate (4.7 g, 16.81 mmol, 86% yield)as a solid, which was used in next step without further purification. MS(m/z): 252/254 (M+H⁺).

To a solution of methyl 5-(4-chlorobenzyl)isoxazole-3-carboxylate (100mg, 0.397 mmol) in THF (5 mL) in an ice bath was added a solution ofNaOH (15.89 mg, 0.397 mmol) in water (5 mL). The mixture was stirred atroom temperature for 2 hours. The solvent was removed in vacuo and theresidue was dissolved in water. The aqueous solution was acidified byaddition of 1N HCl to pH=2-3. The resulting solid which deposited wascollected by filtration and dried in vacuo to give pure5-(4-chlorobenzyl)isoxazole-3-carboxylic acid (90 mg, 0.360 mmol, 91%yield) as a white solid. MS (m/z): 238/240 (M+H⁺).

Preparation 78 5-((Methyl(phenyl)amino)methyl)-1H-pyrazole-3-carboxylicacid

To a mixture of ethyl 1-acetyl-5-methyl-1H-pyrazole-3-carboxylate (2 g,10.19 mmol) and NBS (1.996 g, 11.21 mmol) in CCl₄ (20 mL) was addedbenzoic peroxyanhydride (0.123 g, 0.51 mmol) at room temperaturefollowed by reflux for 5 hours. LCMS showed product with some startingmaterial left. Removed all the solvent and the residue was purified byflash chromatography by solid loading (eluting 0-30% of ethyl acetate inhexane) to afford the product. Combined the fractions and removed allthe solvents to afford the crude product as ethyl1-acetyl-5-(bromomethyl)-1H-pyrazole-3-carboxylate (1.6 g, 5.82 mmol,57.1% yield) MS (m/z) 232/234 (M+H⁺, -Acetyl)

To a solution of N-methylaniline (42.9 mg, 0.4 mmol) in DMF (2 mL) at20° C. was added NaH (21.84 mg, 0.546 mmol). The reaction mixture wasstirred for 5 min. Then ethyl1-acetyl-5-(bromomethyl)-1H-pyrazole-3-carboxylate (100 mg, 0.364 mmol)was added and the mixture were stirred at room temperature for 3 morehours. LCMS indicated the reaction was completed. The reaction wasquenched with drop of water and the solvents were removed to dryness.The crude ethyl1-acetyl-5-((methyl(phenyl)amino)methyl)-1H-pyrazole-3-carboxylate (100mg, 91%) was used for hydrolysis without further purification. MS (m/z)260 (M+H⁺-Acetyl).

To a solution of ethyl1-acetyl-5-((methyl(phenyl)amino)methyl)-1H-pyrazole-3-carboxylate (110mg, 0.365 mmol) in THF (2 mL) was added a solution of LiOH (1.825 mL,3.65 mmol) in water (1.0 mL). The reaction mixture was stirred at roomtemperature for 16 hours and then heated to 50° C. for 4 h at which timeLCMS showed hydrolysis was completed. Cooled to 0° C. and added 1N HCluntil pH=2. The resulting solid was filtered and dried under vacuum. The5-((methyl(phenyl)amino)methyl)-1H-pyrazole-3-carboxylic acid (80 mg,95%) was used as such without further purification. MS (m/z)=231 (M+H⁺⁾

Preparation 79 5-(3-fluorobenzyl)-4H-1,2,4-triazole-3-carboxylic acid

Freshly prepared LiOH (11.03 mL, 22.07 mmol) was added to a stirring,room temperature solution of ethyl5-(3-fluorobenzyl)-4H-1,2,4-triazole-3-carboxylate (1.1 g, 4.41 mmol) inTHF (10 mL) under N₂. The reaction was then stirred at rt for 5 h andLCMS showed the reaction was complete. The reaction was concentrated andthen dissolved in 10.0 mL H₂O. 2N HCl was added dropwise until the pH=4.The white solid that precipitated from the reaction was filtered off andwashed with cold H₂O. The solid was dried under vacuum overnight toobtain title product. 5-(3-fluorobenzyl)-4H-1,2,4-triazole-3-carboxylicacid (750 mg, 3.39 mmol, 77% yield). MS (m/z) 222 (M+H⁺).

Preparation 80 (S)-tert-butyl(1-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-yl)carbamate

To a suspension of NaH (72.1 mg, 1.803 mmol) in THF (25 mL) stirredunder nitrogen at room temp was added a solution of (S)-tert-butyl(2-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-yl)carbamate (500mg, 1.803 mmol) in THF (10 mL) dropwise during 5 min. The reactionmixture was stirred at room temperature for 1 hour and then iodomethane(0.114 mL, 1.821 mmol) was added dropwise during 2 min. The reactionmixture was stirred at room temperature for 36 hours. Reaction wasquenched with water (40 mL) and extracted with EtOAc (3×75 mL). Theorganic layer was dried over anh. Na₂SO₄ and concentrated to provide thecrude product (700 mg). This was purified by silica gel column using25-50% EtOAc in Hexane to afford (S)-tert-butyl(1-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-yl)carbamate(340 mg, 1.162 mmol, 64% yield) as off-white solid. MS (m/z) 192.15([M-BOC]+H⁺).

Preparation 81 (S)-Tert-butyl(1,5-dimethyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-yl)carbamate

To a solution of (S)-tert-butyl(2-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-yl)carbamate (167mg, 0.602 mmol) in DMF (2 mL) was added Cs₂CO₃ (785 mg, 2.409 mmol)followed by MeI (0.113 mL, 1.807 mmol). The reaction mixture was stirredat room temperature overnight. The solution was diluted with EtOAc andwashed with water and brine, dried over Na₂SO₄ and concentrated. Thecrude material was purified by biotage column (10 to 60% EA/Hexane) toprovide (S)-tert-butyl(1,5-dimethyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-yl)carbamate(123 mg, 0.403 mmol, 66.9% yield).

Preparation 82 (S)-tert-butyl(1-methyl-4-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-yl)carbamate

To a suspension (S)-tert-butyl(2-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-yl)carbamate (500mg, 1.803 mmol) and potassium carbonate (336 mg, 2.434 mmol) in acetone(10 mL) was added iodomethane (1.240 mL, 19.83 mmol). The reactionmixture was sealed and heated 80° C. using CEM Microwave operator for 40min. After cooling, to the reaction mixture was filtered andconcentrated under reduced pressure to afford the crude product (600mg). The crude was purified by silica gel (100-200 mesh) flashchromatography using 20-40% ethyl acetate in hexane as an eluent toafford (S)-tert-butyl(1-methyl-4-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-yl)carbamate(390 mg, 1.298 mmol, 72.0% yield). TLC: 30% EtOAc in Hexane; Rf: 0.35.MS (m/z) 290.21 (M+H⁺).

Preparation 83 2-(4-Fluoro-3-nitrophenyl)-5-methyl-1,3,4-oxadiazole

To a suspension of 4-fluorobenzohydrazide (18 g, 117 mmol) in1,1,1-triethoxyethane (85 ml, 467 mmol) was heated at 150° C. Afterrefluxing for 24 hr at 150° C., the reaction solution was cooled down toroom temperature, then a solid precipitated out. After flushing withnitrogen for 2-3 minutes, the resultant solid was treated with 1-2%ethyl ether in hexane. After collecting and washing solid with hexanefollowed by drying in vacuo at 50° C.,2-(4-fluorophenyl)-5-methyl-1,3,4-oxadiazole (17.80 g, 99 mmol, 85%yield) was obtained as light brown solid: MS (m/z) 179.0 (M+H⁺); ¹H NMR(DMSO-d₆) δ: 7.97-8.10 (m, 2H), 7.38-7.51 (m, 2H), 2.58 (s, 3H).

To a suspension (a partial solution, close to dark red color) of2-(4-fluorophenyl)-5-methyl-1,3,4-oxadiazole (2 g, 11.23 mmol) inconcentrated (fuming) H₂SO₄ (8 ml) at 0° C. was added nitric acid (1.394ml, 28.1 mmol) (the solution color was changed to orange yellow). After30 min at 0° C., the reaction solution was poured into cold water(around 300 ml). The resultant solid was collected by filtration andwashed with water. The light tan solid was dried over in a vacuum ovenat 50° C. for overnight to give2-(4-fluoro-3-nitrophenyl)-5-methyl-1,3,4-oxadiazole (2.28 g, 10.22mmol, 91% yield); MS (m/z) 224.0 (M+H⁺); ¹H NMR (DMSO-d₆) δ: 8.61 (dd,J=7.1, 2.3 Hz, 1H), 8.38 (ddd, J=8.8, 4.3, 2.3 Hz, 1H), 7.84 (dd,J=11.1, 8.8 Hz, 1H), 2.62 (s, 3H).

The following intermediates used for the preparation of titled examplecompounds were synthesized using methods analogous to the ones describedabove.

Preparation 84(S)-3-amino-5-methyl-8-(5-methyl-1,3,4-oxadiazol-2-yl)-2,3-dihydrobenzo[b][1,4]oxazepin-4(5H)-one,bis hydrochloride chloride

A mixture of (S)-ethyl3-((tert-butoxycarbonyl)amino)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-8-carboxylate (0.45 g, 1.235 mmol) and anhydroushydrazine (0.465 mL, 14.82 mmol) in EtOH (5.0 mL) was heated to refluxovernight. The solvent was removed in vacuo then the resulting residuewas suspended in ethyl ether, filtered and washed with ethyl etherhaving 5% ethanol to yield (S)-tert-butyl(8-(hydrazinecarbonyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)carbamate(253.0 mg, 58.5%); MS (m/z): 351.3 (M+H⁺).

A suspension of (S)-tert-butyl(8-(hydrazinecarbonyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)carbamate(253.0 mg, 0.722 mmol) in 1,1,1-triethoxyethane (2896 μl, 15.89 mmol)was heated to 150° C. under nitrogen. After 2 h the reaction mixture wascooled to room temperature. On cooling, the solid product precipitatedand was collected by filtration then washed with a small amount of ethylether to give (S)-tert-butyl(5-methyl-8-(5-methyl-1,3,4-oxadiazol-2-yl)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)carbamate(165.0 mg, yield 61%). ¹H NMR (DMSO-d₆) δ: 7.89 (dd, J=8.5, 1.9 Hz, 1H),7.66-7.78 (m, 2H), 7.25 (d, J=6.6 Hz, 1H), 4.42 (br. s., 3H), 3.33 (br.s., 3H), 2.60 (s, 3H), 1.35 (s, 9H); MS (m/z): 375.3 (M+H⁺).

To a solution of (S)-tert-butyl(5-methyl-8-(5-methyl-1,3,4-oxadiazol-2-yl)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)carbamate(165.0 mg, 0.441 mmol) in DCM (3.0 mL) was added a solution of 4M HCl in1,4 dioxane (1.653 mL, 6.61 mmol). The mixture was stirred at roomtemperature for 1 h. The solid product precipitated from the reactionmixture and it was collected by filtration, then washed with ethylether, to yield(S)-3-amino-5-methyl-8-(5-methyl-1,3,4-oxadiazol-2-yl)-2,3-dihydrobenzo[b][1,4]oxazepin-4(5H)-one,bis hydrochloride-chloride salt (150.0 mg, 89%). MS (m/z): 275.1 (M+H⁺).

Preparation 85 Ethyl 2-amino-2-(2-(2-phenylacetyl)hydrazono)acetate

To a solution of 2-phenylacetohydrazide (20 g, 133 mmol) in ethanol (75mL) and diethyl ether (250 mL) was added ethyl 2-ethoxy-2-iminoacetate(20 g, 138 mmol). Stirred at room temperature for 4 hours. A precipitatestarted to form after 10 minutes. The resulting solid was filtered off,rinsed with diethyl ether and dried to give ethyl2-amino-2-(2-(2-phenylacetyl)hydrazono)acetate (27.85 g, yield 82%) as awhite solid, which was used without further purification. MS (m/z) 250(M+H⁺).

Preparation 86 Ethyl 5-benzyl-4H-1,2,4-triazole-3-carboxylate

Ethyl 2-amino-2-(2-(2-phenylacetyl)hydrazono)acetate (27.85 g, 109 mmol)was suspended in xylenes (300 mL) and heated at 170° C. for 24 hourswith a Dean-Stark trap. Initially a very thick mixture formed whichbecame light yellow and homogeneous as the reaction progressed. Thereaction was cooled to room temperature and a solid precipitated out.Diethyl ether was added and the reaction mixture stirred for 15 minutesin an ice/water bath. The solid was filtered off, rinsing with diethylether and hexanes and dried to give ethyl5-benzyl-4H-1,2,4-triazole-3-carboxylate (24.67 g, 95% yield) as a whitesolid, which was used without further purification. MS (m/z) 232 (M+H⁺).

Preparation 87 (S)-tert-butyl(6,8-difluoro-7-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)carbamate

To a solution of 1,3,5-trifluoro-2-methylbenzene (6.0 g, 41.1 mmol) insulfuric acid (46.0 ml, 862 mmol) stirred at −10° C. was added a mixtureof nitric acid (1.835 ml, 41.1 mmol) in sulfuric acid (15.32 ml, 287mmol) dropwise over 10 min. The reaction mixture was stirred at -10 to15° C. for 1.5 hr, at which time TLC indicated starting material wasconsumed. The reaction mixture was poured on to ice-water (500 mL),extracted with DCM (250 mL), and the organic layer was washed with water(100 mL), dried over anh. Na₂SO₄ and concentrated to afford1,3,5-trifluoro-2-methyl-4-nitrobenzene (6.9 g, 31.3 mmol, 76% yield) asyellow liquid. TLC: 20% EtOAc in hexane; Rf: 0.65. GCMS (m/z) 191 (M).

To a solution of 1,3,5-trifluoro-2-methyl-4-nitrobenzene (6.9 g, 36.1mmol) and NaH (2.89 g, 72.2 mmol) in DMF (70 mL) stirred under nitrogenat 0° C. was added a solution of(S)-2-((tert-butoxycarbonyl)amino)-3-hydroxypropanoic acid (7.41 g, 36.1mmol) in DMF (70 mL) dropwise during 5 min. The reaction mixture wasstirred at 0-25° C. for 3 hr at which time TLC indicated startingmaterial was consumed. 0.5M HCl (250 mL) was then added, and the aqueousphase extracted with EtOAc (500 mL). The organic layer was washed withwater (100 mL×2), followed by brine (100 mL). The organic layer wasdried over anh. Na₂SO₄, filtered and concentrated to yield the crude(S)-2-((tert-butoxycarbonyl)amino)-3-(3,5-difluoro-2-methyl-6-nitrophenoxy)propanoicacid and(S)-2-((tert-butoxycarbonyl)amino)-3-(3,5-difluoro-4-methyl-2-nitrophenoxy)propanoicacid (1:1 mixture) (12 g, 32 mmol, 89% yield) as yellow gum. This crudecompound was carried over to next step. TLC: 10% MeOH in DCM; Rf: 0.3.MS (m/z) 375 (M−H⁺).

To a solution of(S)-2-((tert-butoxycarbonyl)amino)-3-(3,5-difluoro-2-methyl-6-nitrophenoxy)propanoicacid compound and(S)-2-((tert-butoxycarbonyl)amino)-3-(3,5-difluoro-4-methyl-2-nitrophenoxy)propanoicacid (1:1) (12 g, 32 mmol) in methanol (250 mL) stirred under nitrogenat room temp was added palladium on carbon (2.55 g, 2.392 mmol)portionwise during 5 min. The contents were stirred under hydrogen at apressure of 60 PSI at 25° C. for 3 hr, at which time TLC indicatedstarting material was consumed. The reaction mixture was filteredthrough a celite pad, washed with excess methanol (300 mL) andconcentrated to provide the crude(S)-3-(2-amino-3,5-difluoro-4-methylphenoxy)-2-((tert-butoxycarbonyl)amino)propanoicacid compound and(S)-3-(2-amino-3,5-difluoro-6-methylphenoxy)-2-((tert-butoxycarbonyl)amino)propanoicacid (1:1 mixture) (9 g, 92% recovery). TLC: 10% MeOH in DCM; Rf: 0.4.This compound was used to next step without further purification.

To a solution of(S)-3-(2-amino-3,5-difluoro-4-methylphenoxy)-2-((tert-butoxycarbonyl)amino)propanoicacid compound and(S)-3-(2-amino-3,5-difluoro-6-methylphenoxy)-2-((tert-butoxycarbonyl)amino)propanoicacid (1:1) (9 g, 26.0 mmol) and DIEA (6.81 mL, 39.0 mmol) in DMSO (90mL) stirred under nitrogen at 20° C. was added HATU (9.88 g, 26.0 mmol)portionwise during 5 min. The reaction mixture was stirred at 25° C. for20 h, at which time TLC indicated starting material was consumed.Reaction was quenched with water (500 mL), extracted with EtOAc (300 mL)and the organic layer was dried over anh. Na₂SO₄, filtered andconcentrated to yield the crude product. This was purified by prep. HPLCto afford a regioisomeric mixture of (S)-tert-butyl(6,8-difluoro-7-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)carbamateand (S)-tert-butyl(6,8-difluoro-9-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)carbamate(1.98 g, 23%) as a pale brown solid. The desired regioisomer wasisolated by chiral HPLC (column: Chiralpak-IC(250*30*5.0p.), mobilephase: n-hexane:IPA (80:20), flow rate: 30 ml/min) of the regioisomericmixture (2.57 g, 7.8 mmol) to afford (S)-tert-butyl(6,8-difluoro-7-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)carbamate(710 mg, 27% recovery) as an off-white solid. ¹H NMR (DMSO-d₆) δ: 9.8(s, 1H), 7.15 (m, 1H), 6.95 (m, 1H), 4.35 (m, 3H), 3.15 (s, 3H), 1.35(s, 9H). MS (m/z) 329 (M+H⁺).

Preparation 88 7-Chloro-9-fluoro-4,5-dihydro-1H-benzo[b]azepin-2(3H)-one

To a solution of 6-chloro-8-fluoro-3,4-dihydronaphthalen-1 (2H)-one (3.2g, 16.11 mmol) in ethanol (32 mL) and water (16 mL) stirred in air atroom temp was added sodium acetate (2.64 g, 32.2 mmol) and hydroxylaminehydrochloride (2.239 g, 32.2 mmol) in one charge. The reaction mixturewas stirred at 100° C. for 1 h. Reaction was monitored by TLC using 20%of ethyl acetate in hexane as mobile phase (twice elution). Oncompletion of the reaction, the reaction mixture was evaporated todryness and 25 mL of water was added. The suspension was stirred for 5min and filtered, washed with water (10 mL), hexane (10 mL) and driedunder vacuum to give 6-chloro-8-fluoro-3,4-dihydronaphthalen-1(2H)-oneoxime (3.35 g, 15.68 mmol, 97% yield) as a pale brown solid, as a 1:1mixture of syn and anti stereoisomers. MS (m/z) 214/216 (M+H⁺).

To a solution of 6-chloro-8-fluoro-3,4-dihydronaphthalen-1(2H)-one oxime(3.2 g, 14.98 mmol) and TEA (6.26 mL, 44.9 mmol) in DCM (90 mL) stirredunder nitrogen at 5° C. was added tosyl-chloride (8.57 g, 44.9 mmol)portionwise during 5 min. The reaction mixture was allowed to stir at rtfor 18 hr. After completion of the reaction (monitored by TLC, 20% ethylacetate in hexane), the reaction mixture was diluted with water,extracted with DCM (2×90 mL). The organic layer was separated and washedwith water (2×50 mL), and the combined organic phases were washed withbrine, dried over anhydrous sodium sulfate and evaporated under reducedpressure to afford the crude product. The crude product was added to asilica gel column and was eluted with Hexane/EtOAc. Collected productfractions: from 5-6% EtOAc elution were concentrated under reducedpressure to afford 6-chloro-8-fluoro-3,4-dihydronaphthalen-1 (2H)-oneO-tosyl oxime (3.0 g, 6.61 mmol, 44.1% yield) as a light brown solid, asa 4:1 unassigned mixture of syn and anti stereoisomers. ¹H NMR (DMSO-d₆)δ: 7.95 (m, 2H), 7.35 (m, 2H), 7.0 (m, 2H), 2.85 (m, 2H), 2.65 (m, 2H),1.8 (m, 2H); MS (m/z) 368/370 (M+H⁺).

To a solution of 6-chloro-8-fluoro-3,4-dihydronaphthalen-1(2H)-oneO-tosyl oxime (3 g, 8.16 mmol) in ethanol (150 mL) and water (80 mL) wasadded potassium acetate (17.61 g, 179 mmol) and reaction mixture wasstirred at 100° C. for 16 h. After the completion of the reaction(monitored the reaction by TLC 30% ethyl acetate in hexane), thereaction mixture was evaporated under reduced pressure to remove theethanol, remaining aqueous layer was further diluted with water (5 mL)and cooled for 30 min at 5° C. The resulting solid precipitate formedwas filtered off, washed with cold water, hexane and dried under vacuumto afford 7-chloro-9-fluoro-4,5-dihydro-1H-benzo[b]azepin-2(3H)-one (1g, 4.16 mmol, 51.0% yield) as brown solid. ¹H NMR (DMSO-d₆) δ: 9.43 (s,1H), 7.35 (d, 1H), 7.22 (s, 1H), 2.75 (m, 2H), 2.15 (m, 4H); MS (m/z)213/215 (M+H⁺).

Example 1 Method A(R)-5-benzyl-N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepin-3-yl)isoxazole-3-carboxamide

To a solution of 5-benzylisoxazole-3-carboxylic acid (208 mg, 0.919mmol) in DCM (30 mL) was addedN1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diaminehydrochloride (129 mg, 0.674 mmol) and 1H-benzo[d][1,2,3]triazol-1-olhydrate (103 mg, 0.674 mmol), then 4-methylmorpholine (0.202 mL, 1.839mmol). Stirred at rt for 5 min, then added(R)-3-amino-5-methyl-2,3-dihydrobenzo[b][1,4]thiazepin-4(5H)-one,hydrochloride (150 mg, 0.613 mmol). The reaction mixture was stirred at25° C. for 5 h. LCMS showed product and the reaction was completed.Removed all the DCM and added 200 ml of EtOAc and the mixture was washedwith water, 0.1N HCl aq, NaHCO₃aq and brine. The organic phase was driedover Na₂SO₄ and concentrated under reduced pressure to afford crudeproduct. ISCO purification (eluting with 0-50% of EtOAc in hexane) toafford the title compound as(R)-5-benzyl-N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepin-3-yl)isoxazole-3-carboxamide.The residue was triturated with ether and hexane. The resulting solidwas filtered and rinsed with hexane and collected (200 mg, 83%). 1H NMR(400 MHz, DMSO-d₆) δ=8.96 (d, J=7.8 Hz, 1H), 7.67 (d, J=7.3 Hz, 1H),7.59 (d, J=4.0 Hz, 2H), 7.44-7.19 (m, 6H), 6.52 (s, 1H), 4.62-4.43 (m,1H), 4.21 (s, 2H), 3.52 (dd, J=6.8, 11.4 Hz, 1H), 3.71-3.44 (m, 1H),3.30 (s, 3H). MS (m/z) 394 (M+H⁺).

Example 2 Method B(R)-5-benzyl-N-(5-methyl-1,1-dioxido-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepin-3-yl)isoxazole-3-carboxamide

To a solution of(R)-5-benzyl-N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepin-3-yl)isoxazole-3-carboxamide(69 mg, 0.175 mmol) in DCM (15 mL) was added 3-chlorobenzoperoxoic acid(101 mg, 0.438 mmol) at 0° C. The reaction mixture was stirred for 1 hrat 0° C. and warmed up to rt, then stirred for 12 hr at rt. The reactionwas quenched with cold 1N aq. NaOH solution. After extraction with DCM,the combined organic solution was washed with 2.5% aq. Na₂S₂O₃ solutionand brine. After drying over MgSO₄, filtration, and concentration, theresidue was subjected to the column chromatography (ISCO 40 g, eluent:5% to 50% EtOAc/Hex) to provide(R)-5-benzyl-N-(5-methyl-1,1-dioxido-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepin-3-yl)isoxazole-3-carboxamide(60 mg, 0.141 mmol, 80% yield) as gum. Trituration with DCM and hexaneto afford the white solid. 1H NMR (400 MHz, DMSO-d₆) δ=9.14 (d, J=7.6Hz, 1H), 8.06-7.90 (m, 2H), 7.81 (d, J=8.1 Hz, 1H),

7.64 (t, J=7.6 Hz, 1H), 7.49-7.19 (m, 5H), 6.52 (s, 1H), 5.76 (s, 1H),4.72 (dt, J=7.5, 11.2 Hz, 1H), 4.22 (s, 2H), 4.14-3.95 (m, 2H), 3.29 (s,3H). MS (m/z) 426 (M+H⁺).

Examples 3 and 4 Method C5-benzyl-N-((1S,3R)-5-methyl-1-oxido-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepin-3-yl)isoxazole-3-carboxamideand5-benzyl-N-((1R,3R)-5-methyl-1-oxido-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepin-3-yl)isoxazole-3-carboxamide

To a solution of(R)-5-benzyl-N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepin-3-yl)isoxazole-3-carboxamide(75 mg, 0.191 mmol) in DCM (15 mL) was added 3-chlorobenzoperoxoic acid(54.8 mg, 0.238 mmol) at 0° C. The reaction mixture was stirred for 1 hrat 0° C. and warmed up to rt, then stirred for 12 hr at rt. The reactionwas quenched with cold 1N aq. NaOH solution. After extraction with DCM,the combined organic solution was washed with 2.5% aq. Na₂S₂O₃ solutionand brine. After drying over MgSO₄, filtration, and concentration, theresidue was subjected to the column chromatography (ISCO 40 g, eluent:0% to 40%, then to 60% EtOAc/Hex) to provide 2 isomers as5-benzyl-N-((1R,3R)-5-methyl-1-oxido-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepin-3-yl)isoxazole-3-carboxamide(64 mg, 0.156 mmol, 82% yield)) and5-benzyl-N-((1S,3R)-5-methyl-1-oxido-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepin-3-yl)isoxazole-3-carboxamide(14 mg, 0.034 mmol, 17.94% yield.5-benzyl-N-((1S,3R)-5-methyl-1-oxido-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepin-3-yl)isoxazole-3-carboxamide.MS (m/z) 410 (M+H⁺). 1H NMR (400 MHz, DMSO-d₆) δ=9.06 (d, J=7.8 Hz, 1H),7.88-7.75 (m, 1H), 7.73-7.63 (m, 2H), 7.55-7.44 (m, 1H), 7.42-7.20 (m,4H), 6.54 (s, 1H), 5.76 (s, 1H), 4.73 (dt, J=7.6, 11.1 Hz, 1H), 4.22 (s,2H), 3.83 (dd, J=7.5, 14.5 Hz, 1H), 3.53 (dd, J=11.1, 14.4 Hz, 1H), 3.25(s, 3H).5-benzyl-N-((1R,3R)-5-methyl-1-oxido-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepin-3-yl)isoxazole-3-carboxamide.MS (m/z) 410 (M+H⁺). ¹H NMR (DMSO-d₆) 8.89-9.19 (m, 1H), 7.56-7.86 (m,4H), 7.22-7.48 (m, 5H), 6.51 (s, 1H), 4.45-4.65 (m, 2H), 4.13-4.35 (m,3H), 3.30 (s, 3H).

Example 5 Method D3-Benzyl-N—((S)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)piperidine-1-carboxamide

To a suspension of(S)-3-amino-5-methyl-2,3-dihydrobenzo[b][1,4]oxazepin-4(5H)-one,hydrochloride (100 mg, 0.437 mmol) and Et₃N (0.152 ml, 1.093 mmol) inTHF (4 ml) was added 4-nitrophenyl carbonochloridate (97 mg, 0.481 mmol)at 0° C. After 45 min, 3-benzylpiperidine (0.085 ml, 0.481 mmol) andEt₃N (0.091 ml, 0.656 mmol) were added and warmed up to rt. After 2 hrat rt, the reaction mixture was concentrated, then diluted withMeOH-DMSO (2 mL, 1:1). After filtration through Acrodisc CR 25 mmsyringe filter with 0.2 uM PTFE membrane, the solution was purified byHPLC (Waters, column: Waters Sunfire 30×150 mm, eluent:Acetonitrile:Water TFA 50-100%, flow rate: 50 ml/min) to give3-benzyl-N—((S)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)piperidine-1-carboxamide(52.2 mg, 0.123 mmol, 28.2% yield, unoptimized) as a mixture ofdiastereomers. MS (m/z) 393.9 (M+H⁺). After separation using a chiralcolumn (Chiralpak IA-H, eluent: Co-solvent: IPA, % Co-solvent: 30%Isocratic, Flow rate=4 mL/min), two diastereomers were obtained withoutassigning the absolute stereochemistry at the C-3 piperdine. Isomer A(9.9 mg): ¹H NMR (CDCl₃) δ: 7.14-7.36 (m, 9H), 5.50 (d, J=6.3 Hz, 1H),4.86 (dt, J=11.1, 6.8 Hz, 1H), 4.63 (dd, J=9.7, 7.5 Hz, 1H), 4.16 (dd,J=11.2, 9.7 Hz, 1H), 3.87 (dt, J=13.1, 1.6 Hz, 1H), 3.72-3.81 (m, 1H),3.43 (s, 3H), 2.88 (ddd, J=12.9, 11.4, 3.2 Hz, 1H), 2.52-2.69 (m, 2H),2.45 (dd, J=13.6, 8.1 Hz, 1H), 1.65-1.81 (m, 3H), 1.36-1.46 (m, 1H),1.06-1.18 (m, 1H). MS (m/z) 393.9 (M+H⁺). Isomer B (13.9 mg): ¹H NMR(CDCl₃) δ: 7.09-7.73 (m, 9H), 5.51 (br. s., 1H), 4.79-4.92 (m, 1H),4.59-4.70 (m, 1H), 4.10-4.20 (m, 1H), 3.89 (m, 1H), 3.77 (m, 1H), 3.42(s, 3H), 2.77-2.93 (m, 1H), 2.40-2.67 (m, 3H), 1.63-1.81 (m, 3H),1.38-1.49 (m, 1H), 1.06-1.20 (m, 1H). MS (m/z) 393.9 (M+H⁺).

Example 6 Method E(S)-5-Benzyl-N-(8-(2-methoxyethoxy)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)isoxazole-3-carboxamide

Polymer bound PPh₃ (1.6 mmol/g loading, 2.5 eq, 268 mg),(S)-5-benzyl-N-(8-hydroxy-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)isoxazole-3-carboxamide(65 mg, 0.171 mmol) and 2-methoxyethanol (0.027 mL, 0.343 mmol) werecombined in THF (3 mL). Next added di-tert-butyl azodicarboxylate (79mg, 0.343 mmol) and stirred mixture at rt for 20 hours. TFA (0.066 mL,0.857 mmol) was added and mixture was stirred for 1 hour. Reaction wasfiltered through Celite, rinsing with 10% MeOH/DCM and concentrated.Crude was partitioned between DCM and satd. NaHCO₃ and layers wereseparated. Organics were concentrated and purified by flashchromatography, Biotage (4 g silica column; 0.5-3% MeOH/DCM (plusNH₄OH), 15 min.) to give 37 mg white foam in 48% yield. ¹H NMR (DMSO-d₆)δ: 9.92 (s, 1H), 8.77 (d, J=8.1 Hz, 1H), 7.25-7.40 (m, 5H), 7.02 (d,J=8.8 Hz, 1H), 6.70-6.79 (m, 2H), 6.57 (s, 1H), 4.80 (dt, J=10.8, 7.4Hz, 1H), 4.50 (t, J=10.6 Hz, 1H), 4.41 (dd, J=10.5, 6.7 Hz, 1H), 4.23(s, 2H), 4.01-4.13 (m, 2H), 3.60-3.68 (m, 2H), 3.30 (s, 3H); MS (m/z)438.3 (M+H⁺).

Example 75-Benzyl-N-(1-hydroxy-5-methyl-4-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-3-yl)isoxazole-3-carboxamide

Benzyl (2,5-dioxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-3-yl)carbamate(400 mg, 1.233 mmol) was dissolved in 10 mL of THF, and then Cs₂CO₃ (1.0g, 3.08 mmol) was added, followed by methyl iodide (0.116 mL, 1.850mmol). The reaction mixture was maintained at room temperature for 16hours. The mixture was then filtered. The filtrate was concentrated, andthen purified by Isco Combiflash (15%-80% EtOAc/Hexane; 40 g IscoRediSep column). The fractions containing the product were combined andconcentrated to give benzyl(1-methyl-2,5-dioxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-3-yl) carbamateas a yellow oil (290 mg, 70% yield). 1H NMR (CDCl₃) d ppm 7.53-7.72 (m,2H), 7.26-7.44 (m, 6H), 7.21 (d, J=8.1 Hz, 1H), 6.14 (d, J=6.6 Hz, 1H),5.02-5.18 (m, 2H), 4.95 (ddd, J=12.6, 6.6, 4.0 Hz, 1H), 3.38 (s, 3H),3.33 (dd, 1H), 2.94 (dd, J=19.3, 12.8 Hz, 1H); MS (m/z): 339 (M+H⁺).

Benzyl (1-methyl-2,5-dioxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-3-yl)carbamate (290 mg, 0.857 mmol) was dissolved in ethanol (20 mL).Palladium on Carbon (10 wt % loading, 91 mg, 0.857 mmol) was added. Thereaction mixture was maintained at room temperature for 3 h under ahydrogen balloon. The reaction mixture was filtered and the filtrate wasconcentrated to a yellow oil, which was then turned into white solidupon standing under high vacuum for 16 h to yield3-amino-1-methyl-3,4-dihydro-1H-benzo[b]azepine-2,5-dione (158 mg, 90%yield). 1H NMR (MeOH-d4) d ppm 7.60-7.88 (m, 2H), 7.23-7.59 (m, 2H),4.50-4.72 (m, 1H), 3.43 (s, 3H), 3.11-3.38 (m, 1H), 2.08-2.31 (m, 1H);MS (m/z): 205 (M+H⁺).

5-Benzylisoxazole-3-carboxylic acid (29.8 mg, 0.147 mmol) was dissolvedin DCM(2 mL), and then N-hydroxybenzotriazole (24.75 mg, 0.162 mmol) andEDC (31.0 mg, 0.162 mmol) were added. The mixture was maintained at roomtemperature for 10 min. N-methylmorpholine (0.057 mL, 0.514 mmol) and3-amino-5-methyl-2,3-dihydro-1H-benzo[b]azepine-1,4(5H)-dione (30 mg,0.147 mmol) were then added. The reaction mixture was maintained at roomtemperature for 16 h. The mixture was then concentrated and the residuewas purified by Isco Combiflash (10%-50% EtOAc/Hexane; 24 g Isco RediSepcolumn). The fractions containing the product were combined andconcentrated to give5-benzyl-N-(5-methyl-1,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-3-yl)isoxazole-3-carboxamidas a clear oil, which turned into a white solid upon standing under highvacuum for 16 h (42 mg, 73% yield). 1H NMR (400 MHz, CDCl₃) δ ppm 3.00(dd, J=19.33, 12.76 Hz, 1H) 3.39-3.48 (m, 4H) 4.13 (s, 2H) 5.26 (ddd,J=12.76, 6.44, 3.79 Hz, 1H) 6.35 (s, 1H) 7.19-7.43 (m, 7H) 7.55-7.72 (m,2H) 7.99 (d, J=6.57 Hz, 1H); MS (m/z): 390 (M+H⁺).

5-Benzyl-N-(5-methyl-1,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-3-yl)isoxazole-3-carboxamide(20 mg, 0.051 mmol) was dissolved in 2 mL of MeOH, and then NaBH4 (2.91mg, 0.077 mmol) was added at rt. The mixture was maintained at rt for 16h. The mixture was then concentrated and partitioned betweensat.NaHCO₃(aq) and DCM. The organic layer was concentrated and theresidue was purified by Isco Combiflash (1%-10% MeOH/CH₂Cl₂, 10% NEt3 inMeOH; 4 g RediSep column). Collected fractions containing the productwere combined and concentrated to give5-benzyl-N-(1-hydroxy-5-methyl-4-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-3-yl)isoxazole-3-carboxamideas a clear oil (14 mg, 70% yield). ¹H NMR (400 MHz, CDCl₃) δ ppm 2.34(d, J=4.55 Hz, 1H) 2.44 (ddd, J=12.13, 10.86, 7.58 Hz, 1H) 2.67 (td,J=11.68, 8.21 Hz, 1H) 3.43 (s, 3H) 4.12 (s, 2H) 4.51 (dt, J=10.48, 7.89Hz, 1H) 5.06 (t, J=3.66 Hz, 1H) 6.32 (s, 1H) 7.13-7.45 (m, 8H) 7.67 (dd,J=6.69, 2.15 Hz, 1H) 7.81 (d, J=7.07 Hz, 1H); MS (m/z): 392 (M+H⁺).

Example 8(S)-5-benzyl-N-(5-methyl-4-oxo-7-(1H-tetrazol-5-yl)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)isoxazole-3-carboxamide

Step 1:(S)-5-benzyl-N-(7-(1-(2-cyanoethyl)-1H-tetrazol-5-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)isoxazole-3-carboxamide.To a solution of(S)-3-(5-benzylisoxazole-3-carboxamido)-N-(2-cyanoethyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-7-carboxamide(69.0 mg, 0.146 mmol) and pyridine (0.071 mL, 0.874 mmol) in DCM (2.0mL) was added phosphorus pentachloride (45.5 mg, 0.219 mmol). Thereaction mixture was heated to reflux for 3.0 hr then additional 0.25 eqPCl₅ was added. The reaction mixture was cooled to rt then TMSN₃ (0.110mL, 0.831 mmol) was added and the reaction mixture was stirred overnightat rt. At 20 h, additional 4.0 eq. of TMS-N₃ and 3.0 eq. pyridine wereadded to the reaction mixture. The reaction mixture was carefullyquenched with a few drops of sat. aq. NaHCO₃ followed after 5 min withexcess NaHCO₃. The mixture was stirred for 15 min. The organic phase wasseparated and washed with 10% aq citric acid and brine. The organicphase was dried over Na₂SO₄, filtered and concentrated in vacuo. Theresidue was purified by FCC (EtOAc-Hex: 50-70%). MS (m/z) 499.3 (M+H⁺).

Step 2:(S)-5-benzyl-N-(5-methyl-4-oxo-7-(1H-tetrazol-5-yl)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)isoxazole-3-carboxamide.To a solution of(S)-5-benzyl-N-(7-(1-(2-cyanoethyl)-1H-tetrazol-5-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)isoxazole-3-carboxamide(42.0 mg, 0.084 mmol) in THF (2.0 mL) was added 2.0 M NaOH (0.051 mL,0.101 mmol). The reaction mixture was stirred for 2 h then quenched withcold 1N HCl and extracted with EtOAc. The organic phase was washed withbrine, dried over Na₂SO₄, filtered then concentrated in vacuo. The solidproduct obtained was used without further purification (36.0 mg, 96%).¹H NMR (DMSO-d₆) δ: 8.92 (d, J=8.1 Hz, 1H), 8.12 (d, J=2.0 Hz, 1H), 7.94(dd, J=8.3, 2.3 Hz, 1H), 7.46 (d, J=8.3 Hz, 1H), 7.25-7.39 (m, 6H), 6.55(s, 1H), 4.87-4.96 (m, 1H), 4.67 (dd, J=11.6, 10.1 Hz, 1H), 4.49 (dd,J=9.9, 7.6 Hz, 1H), 4.22 (s, 2H), 3.39 (s, 3H). MS (m/z) 446.3 (M+H⁺).

Example 9(S)-3-(5-benzylisoxazole-3-carboxamido)-5-methyl-N-(methylsulfonyl)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-7-carboxamide

To a suspension of(S)-3-(5-benzylisoxazole-3-carboxamido)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-7-carboxylic acid (60.0 mg, 0.142 mmol) in DCM(2.0 mL) was added 1-chloro-N,N,2-trimethylprop-1-en-1-amine (22.83 mg,0.171 mmol) as a solution in DCM (0.10 ml) dropwise over 1 min. Thereaction mixture was stirred at rt for 1 h and became a homogeneoussolution. This mixture was added dropwise to a mixture ofmethanesulfonamide (54.2 mg, 0.570 mmol), TEA (0.079 mL, 0.570 mmol) andDMAP (1.044 mg, 8.54 μmol) in 1.0 mL DCM and stirring was continued over2 h at rt. The reaction mixture was diluted with EtOAc, then washed with10% aq citric acid, water and brine. The organic phase was dried overNa₂SO₄, filtered then concentrated in vacuo. The residue was purified byFCC[MeOH-DCM: 0-4.0%] to yield the desired product (26.0 mg, 36.6%). ¹HNMR (DMSO-d₆) δ: 8.82 (d, J=8.1 Hz, 1H), 7.95 (d, J=1.8 Hz, 1H), 7.83(dd, J=8.3, 2.0 Hz, 1H), 7.25-7.38 (m, 6H), 7.20 (d, J=8.1 Hz, 1H), 6.56(s, 1H), 4.84 (dt, J=11.6, 7.8 Hz, 1H), 4.59 (dd, J=11.7, 10.0 Hz, 1H),4.42 (dd, J=9.7, 7.7 Hz, 1H), 4.22 (s, 2H), 3.32 (br. s., 3H), 2.95 (s,3H). MS (m/z) 499.1 (M+H⁺).

Example 10 Method F(S)-5-benzyl-N-(7-fluoro-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)isoxazole-3-carboxamide

To a solution of 5-benzylisoxazole-3-carboxylic acid (79 mg, 0.390 mmol)and DIEA (0.186 mL, 1.064 mmol) in DMSO (1 mL) was added HATU (135 mg,0.355 mmol) in one portion. After stirring at rt for 5 min, a solutionof (S)-3-amino-7-fluoro-2,3-dihydrobenzo[b][1,4]oxazepin-4(5H)-one,trifluoroacetic acid salt (110.0 mg, 0.355 mmol) in DMSO (1 mL) wasadded dropwise to the mixture. The reaction was allowed to stir at rtfor 2 h. LCMS analysis indicated starting material still remained. Anadditional amount of DIEA (0.20 mL) and HATU (0.11 g) were added and thereaction allowed to stir for 2 h. The reaction mixture was diluted withEtOAc then washed with water (3×), NH₄Cl and brine. After drying thesolution over Na₂SO₄ and concentrating in vacuo, the residue waspurified by FCC [EtOAc/Hex: 25-60%] to yield the desired product (50 mg,37%). ¹H NMR (DMSO-d₆) δ: 10.21 (s, 1H), 8.88 (d, J=8.1 Hz, 1H),7.25-7.40 (m, 5H), 7.17 (dd, J=8.6, 5.6 Hz, 1H), 6.92-7.00 (m, 2H),6.55-6.59 (m, 1H), 4.83 (dt, J=10.5, 7.5 Hz, 1H), 4.38-4.53 (m, 2H),4.23 (s, 2H). MS (m/z) 382.9 (M+H⁺).

Example 11 Method G(S)-5-benzyl-N-(7-(3-isopropylureido)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)isoxazole-3-carboxamide

To a solution of(S)—N-(7-amino-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-5-benzylisoxazole-3-carboxamide(50.0 mg, 0.112 mmol) in DMF (0.50 mL) at 0° C. was added2-isocyanatopropane (0.023 mL, 0.235 mmol). After 2 d, additional2-isocyanatopropane (0.023 mL, 0.235 mmol) was added and the reactionwas continued. The reaction mixture was diluted with EtOAc then it waswashed in succession with sat. NH₄Cl, water, and brine. The organicphase was dried over Na₂SO₄, filtered then concentrated in vacuo. Theresidue was purified by FCC [EtOAc/Hex-45-80%]. ¹H NMR (DMSO-d₆) δ: 8.83(d, J=8.3 Hz, 1H), 8.44 (s, 1H), 7.57 (d, J=2.5 Hz, 1H), 7.25-7.38 (m,5H), 7.12-7.16 (m, 1H), 7.05-7.09 (m, 1H), 6.55 (s, 1H), 6.06 (d, J=7.6Hz, 1H), 4.83 (dt, J=11.4, 8.1 Hz, 1H), 4.46-4.53 (m, 1H), 4.33 (dd,J=9.9, 7.8 Hz, 1H), 4.22 (s, 2H), 3.71-3.81 (m, 1H), 3.26 (s, 3H), 1.11(s, 3H), 1.09 (s, 3H). MS (m/z) 478.2 (M+H⁺).

Example 12 Method H(S)-5-benzyl-N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4H-1,2,4-triazole-3-carboxamide

A mixture of(S)-3-amino-5-methyl-2,3-dihydrobenzo[b][1,4]oxazepin-4(5H)-one,hydrochloride (4.00 g, 16.97 mmol),5-benzyl-4H-1,2,4-triazole-3-carboxylic acid, hydrochloride (4.97 g,18.66 mmol) and DIEA (10.37 mL, 59.4 mmol) in isopropanol (150 mL) wasstirred vigorously for 10 minutes and then2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane 2,4,6-trioxide (T3P)(50% by wt. in EtOAc) (15.15 mL, 25.5 mmol) was added. The mixture wasstirred at rt for 10 minutes and then quenched with water andconcentrated to remove isopropanol. The resulting crude material isdissolved in EtOAc and washed with 1M HCl, satd. NaHCO₃ and brine.Organics were concentrated and purified by column chromatography (220 gsilica column; 20-90% EtOAc/hexanes, 15 min.; 90%, 15 min.) to give thetitle compound as a light orange foam (5.37 g, 83%). ¹H NMR (MeOH-d4) δ:7.40-7.45 (m, 1H), 7.21-7.35 (m, 8H), 5.01 (dd, J=11.6, 7.6 Hz, 1H),4.60 (dd, J=9.9, 7.6 Hz, 1H), 4.41 (dd, J=11.4, 9.9 Hz, 1H), 4.17 (s,2H), 3.41 (s, 3H); MS (m/z) 378.3 (M+H⁺).

Alternative Preparation:

To a solution of(S)-3-amino-5-methyl-2,3-dihydrobenzo[b][1,4]oxazepin-4(5H)-onehydrochloride (100 g, 437 mmol), 5-benzyl-4H-1,2,4-triazole-3-carboxylicacid hydrochloride (110 g, 459 mmol) in DCM (2.5 L) was added DIPEA(0.267 L, 1531 mmol) at 15° C. The reaction mixture was stirred for 10min. and 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane 2,4,6-trioxide≥50 wt. % in ethyl acetate (0.390 L, 656 mmol) was slowly added at 15°C. After stirring for 60 mins at RT the LCMS showed the reaction wascomplete, upon which time it was quenched with water, partitionedbetween DCM and washed with 0.5N HCl aq (2 L), saturated aqueousNaHCO₃(2 L), brine (2 L) and water (2 L). The organic phase wasseparated and activated charcoal (100 g) and sodium sulfate (200 g) wereadded. The dark solution was shaken for 1 h before filtering. Thefiltrate was then concentrated under reduced pressure to afford theproduct as a tan foam (120 g). The product was dried under a high vacuumat 50° C. for 16 h. ¹H NMR showed 4-5% wt of ethyl acetate present. Thesample was dissolved in EtOH (650 ml) and stirred for 30 mins, afterwhich the solvent was removed using a rotavapor (water-bath T=45° C.).The product was dried under high vacuum for 16 h at RT (118 g, 72%yield). The product was further dried under high vacuum at 50° C. for 5h. ¹H NMR showed <1% of EtOH and no ethyl acetate. ¹H NMR (400 MHz,DMSO-d₆) δ ppm 4.12 (s, 2H), 4.31-4.51 (m, 1H), 4.60 (t, J=10.36 Hz,1H), 4.83 (dt, J=11.31, 7.86 Hz, 1H), 7.12-7.42 (m, 8H), 7.42-7.65 (m,1H), 8.45 (br. s., 1H), 14.41 (br. s., 1H). MS (m/z) 378 (M+H⁺).

Crystallization:

(S)-5-Benzyl-N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4H-1,2,4-triazole-3-carboxamide(100 mg) was dissolved in 0.9 mL of toluene and 0.1 mL ofmethylcyclohexane at 60° C., then stirred briskly at room temperature(20° C.) for 4 days. After 4 days, an off-white solid was recovered (76mg, 76% recovery). The powder X-ray diffraction (PXRD) pattern of thismaterial is shown in FIG. 7 and the corresponding diffraction data isprovided in Table 1.

The PXRD analysis was conducted using a PANanalytical X'Pert Prodiffractometer equipped with a copper anode X-ray tube, programmableslits, and X'Celerator detector fitted with a nickel filter. Generatortension and current were set to 45 kV and 40 mA respectively to generatethe copper Ku radiation powder diffraction pattern over the range of2-40° 2θ. The test specimen was lightly triturated using an agate mortarand pestle and the resulting fine powder was mounted onto a silicon zerobackground plate.

TABLE 1 Diffraction Angle (°2θ) 5.70 8.46 11.46 16.36 17.10 19.82 21.6322.03 23.11 23.75 24.35 24.94

Example 13 Method I(S)-5-benzyl-N-(2-oxo-7-(1H-pyrazol-3-yl)-2,3,4,5-tetrahydro-1H-benzo[b]azepin-3-yl)-4H-1,2,4-triazole-3-carboxamide

(S)-5-benzyl-N-(7-bromo-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-3-yl)-4H-1,2,4-triazole-3-carboxamide(60 mg, 0.136 mmol), tert-butyl3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylate(40.1 mg, 0.136 mmol), Pd(PPh₃)₄(29.8 mg, 0.026 mmol) and K₂CO₃ (107 mg,0.775 mmol) were mixed inl,4-dioxane (2 mL) and water (1 mL). Thereaction mixture was put in an Emrys Optimizer (150 W, absorptionnormal) and microwaved at 130° C., for 20 min. The reaction mixture wasfiltered and the filtrate was concentrated. The residue was purified byreverse phase HPLC (Waters Sunfire 30×150 mm, 26-60% CH₃CN:H₂O (0.1%TFA), 50 mg/mL). Collected fractions containing the product werecombined, neutralized by NaHCO₃, and then concentrated to give thedesired product as a white solid (6 mg, 11% yield). ¹H NMR (DMSO-d₆) δppm 10.05 (s, 1H), 8.31 (br. s., 1H), 7.77 (s, 1H), 7.65-7.75 (m, 2H),7.19-7.42 (m, 5H), 7.07 (d, J=8.0 Hz, 1H), 6.71 (d, J=1.5 Hz, 1H), 4.38(dt, J=11.2, 7.9 Hz, 1H), 4.12 (s, 2H), 2.66-2.90 (m, 2H), 2.42-2.51 (m,1H), 2.28 (br. s., 1H); MS (m/z): 428 (M+H⁺).

Example 14(S)-3-(5-benzylisoxazole-3-carboxamido)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-7-carboxylicacid

To a solution of (S)-methyl3-(5-benzylisoxazole-3-carboxamido)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-7-carboxylate(332 mg, 0.762 mmol) in THF (6 mL)/Water (2.0 mL) was added LiOH (1.144mL, 1.144 mmol) as a solution in water. Reaction was stirred at rt forabout 2 h. The reaction mixture was diluted with water then extractedwith EtOAc twice. The aqueous phase was acidified to pH-3.0 then it wasextracted with EtOAc. The latter organic phase was dried over Na₂SO₄then filtered and concentrated in vacuo to yield the desired product asa solid. The solid was warmed in toluene then decanted to give the finalsolid product that was used directly in the next step. ¹H NMR (DMSO-d₆)δ: 13.18 (br. s., 1H), 8.87 (d, J=8.1 Hz, 1H), 7.98 (d, J=2.0 Hz, 1H),7.85 (dd, J=8.3, 2.0 Hz, 1H), 7.25-7.38 (m, 6H), 6.55 (s, 1H), 4.87 (dt,J=11.8, 7.7 Hz, 1H), 4.64 (dd, J=11.6, 10.1 Hz, 1H), 4.46 (dd, J=9.9,7.6 Hz, 1H), 4.22 (s, 2H). MS (m/z) 422.3 (M+H⁺).

Example 15 Method J(S)—N-(7-acetamido-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-5-benzylisoxazole-3-carboxamide

(S)—N-(7-acetamido-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-5-benzylisoxazole-3-carboxamide.To a solution of(S)—N-(7-amino-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-5-benzylisoxazole-3-carboxamide(60.0 mg, 0.153 mmol) in THF (2.0 mL) at 0° C. was added DIEA (0.061 mL,0.352 mmol) then AcCl (10.87 μL, 0.153 mmol). The reaction mixture wasmonitored by LCMS. Reaction showed desired mass after 10 min with all smconsumed. The reaction mixture was concentrated to a solid residue. Thesolid was suspended in small amount of DCM and 1 mL of 25% EtOAc/Hex.The suspension was lightly warmed then cooled and filtered to collectthe solid product. The solid was washed with ethyl ether. yield=56 mgsolid powder; NMR shows much impurity, so the sample was subjected toFCC [MeOH-DCM:0-3.0%]. yield=18 mg. ¹H NMR (DMSO-d₆) δ: 10.11 (s, 1H),8.86 (d, J=8.1 Hz, 1H), 7.71 (d, J=2.3 Hz, 1H), 7.25-7.42 (m, 6H), 7.15(d, J=8.6 Hz, 1H), 6.55 (s, 1H), 4.84 (dt, J=11.6, 8.0 Hz, 1H),4.49-4.56 (m, 1H), 4.35 (dd, J=9.9, 7.8 Hz, 1H), 4.22 (s, 2H), 3.27 (s,3H), 2.06 (s, 3H). MS (m/z) 435.3 (M+H⁺).

Example 16 Method K(S)-(3-(5-benzyl-4H-1,2,4-triazole-3-carboxamido)-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-7-yl)boronicacid

(S)-5-benzyl-N-(2-oxo-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3,4,5-tetrahydro-1H-benzo[b]azepin-3-yl)-4H-1,2,4-triazole-3-carboxamide(65 mg, 0.133 mmol) was dissolved in 2 mL THF, and then sodium periodate(28.5 mg, 0.133 mmol) was added, followed by HCl (1N in H₂O, 0.041 mL,1.334 mmol). The mixture was maintained at rt for 2 h. The mixture wasthen concentrated and the residue was purified by Isco Combiflash(2%-10% MeOH/CH₂Cl₂, 10% NEt3 in MeOH; 40 g RediSep column). Collectedfractions containing the product were combined and concentrated to givethe desired product as a colorless oil, which was then lyophilized to awhite solid (36 mg, 67% yield). ¹H NMR (400 MHz, MeOD-d4) δ ppm2.11-2.32 (m, 1H) 2.57-2.74 (m, 1H) 2.74-2.89 (m, 1H) 2.97 (td, J=13.33,7.96 Hz, 1H) 4.12-4.22 (m, 2H) 4.49-4.65 (m, 1H) 6.98-7.17 (m, 1H)7.19-7.43 (m, 5H) 7.51-7.66 (m, 1H) 7.71 (br. s., 1H); MS (m/z): 406(M+H⁺).

Example 17(S)-(3-(3-benzyl-1H-pyrazole-5-carboxamido)-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-8-yl)boronicacid

To a mixture of(S)-3-amino-8-bromo-4,5-dihydro-1H-benzo[b]azepin-2(3H)-one (1.0 g, 3.92mmol) in DCM (30 mL) was added TEA (0.820 mL, 5.88 mmol) and BOC₂O(0.956 mL, 4.12 mmol). Mixture was stirred at room temperature for 1.5hours and a solid precipitated out. Water was added and the mixture wasstirred for 5 minutes and solid was filtered and dried to give 869 mg of(S)-tert-butyl(8-bromo-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-3-yl)carbamate as apale yellow solid. Layers of the filtrate were separated and organicswere concentrated to a solid. Solid was triturated in diethyl ether,filtered and dried to give 390 mg pale yellow solid. Yield=87%. ¹H NMR(DMSO-d₆) δ: 9.81 (s, 1H), 7.29-7.33 (m, 1H), 7.24 (d, J=8.1 Hz, 1H),7.18 (d, J=1.8 Hz, 1H), 7.05 (d, J=8.3 Hz, 1H), 3.86 (dt, J=12.0, 8.1Hz, 1H), 2.56-2.72 (m, 2H), 2.19 (m, 1H), 2.06 (td, J=12.3, 7.3 Hz, 1H),1.34 (s, 9H); MS (m/z) 355/357 (bromine splitting pattern) (M+H⁺).

Nitrogen was bubbled through a mixture of (S)-tert-butyl(8-bromo-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-3-yl)carbamate (385mg, 1.084 mmol), potassium acetate (532 mg, 5.42 mmol) andbis(pinacolato)diboron (330 mg, 1.301 mmol) in 1,4-Dioxane (10 mL) for 5min. Then PdCl2(dppf)-CH₂C₁₂ adduct (89 mg, 0.108 mmol) was added andmixture was heated at 95° C. for 2 hours. Reaction was cooled to roomtemperature, diluted with water and ethyl acetate and filtered through aCelite plug. Layers of filtrate were separated. Organics wereconcentrated and purified by Biotage (10 g silica column, 10-50% E/H, 10min.; 70%, 5 min.) to give 344 mg of (S)-tert-butyl(2-oxo-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3,4,5-tetrahydro-1H-benzo[b]azepin-3-yl)carbamateas a tan solid in 77% yield. ¹H NMR (DMSO-d₆) δ: 9.70 (s, 1H), 7.41 (d,J=7.3 Hz, 1H), 7.28-7.33 (m, 2H), 7.00 (d, J=8.3 Hz, 1H), 3.83 (dt,J=11.9, 8.3 Hz, 1H), 2.68 (m, 2H), 2.18 (m, 1H), 2.08 (m, 1H), 1.34 (s,9H), 1.30 (s, 12H); MS (m/z) 403.4 (M+H⁺).

To a mixture of (S)-tert-butyl(2-oxo-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3,4,5-tetrahydro-1H-benzo[b]azepin-3-yl)carbamate(70 mg, 0.174 mmol) in DCM (3 mL) was added 4.0 M HCl in dioxane (218μl, 0.870 mmol). Mixture was stirred at room temperature for 2 days,concentrated to remove solvents to yield(S)-3-benzyl-N-(2-oxo-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3,4,5-tetrahydro-1H-benzo[b]azepin-3-yl)-1H-pyrazole-5-carboxamidewhich was used as-is in the next step. MS (m/z) 303.3 (M+H⁺).

A solution of 3-benzyl-1H-pyrazole-5-carboxylic acid (38.7 mg, 0.191mmol) and HATU (79 mg, 0.209 mmol) in CH₃CN (1 mL) and DMSO (0.3 mL) wasstirred for 40 minutes. Then it was added to a mixture ofN-methylmorpholine (0.067 mL, 0.609 mmol) and(S)-3-amino-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4,5-dihydro-1H-benzo[b]azepin-2(3H)-one(from the prior step) in CH₃CN (1 mL). The mixture was stirred at roomtemperature for 40 minutes. Water (5 mL) was slowly added while stirringvigorously. A solid precipitated out and it was stirred for 5 minutes,filtered and dried to give 60 mg light brown solid in 70% yield. ¹H NMR(MeOH-d4) δ: 7.58 (d, J=7.3 Hz, 1H), 7.46 (s, 1H), 7.27-7.37 (m, 4H),7.19-7.26 (m, 4H), 6.49 (br. s., 1H), 4.54 (dd, J=11.6, 8.1 Hz, 1H),4.02 (s, 2H), 2.98 (td, J=13.2, 8.0 Hz, 1H), 2.75-2.83 (m, 1H), 2.61 (m,1H), 2.16-2.28 (m, 1H), 1.36 (s, 12H); MS (m/z) 487.5 (M+H⁺).

To a solution of(S)-3-benzyl-N-(2-oxo-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3,4,5-tetrahydro-1H-benzo[b]azepin-3-yl)-1H-pyrazole-5-carboxamide(45 mg, 0.093 mmol) in THF (2 mL) was added benzeneboronic acid, polymerbound [5 eq, 0.46 mmol, 170 mg (assuming 2.6 mmol/g loading), 2.6-3.2mmol/g loading] and conc. HCl (0.039 mL, 0.463 mmol). Mixture wasstirred at room temperature for 3 days. Reaction was not quite complete,so more benzeneboronic acid, polymer bound (50 mg) was added and mixturewas stirred for another 4 hours, then filtered to remove resin andconcentrated. Water (3 mL) was added and a solid formed. Solid wasfiltered and purified by column chromatography (4 g silica column;50-100% ethyl acetate/hexanes, then 10% methanol/ethyl acetate) to give9 mg of(S)-(3-(3-benzyl-1H-pyrazole-5-carboxamido)-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-8-yl)boronicacid as an off-white solid in 33% yield. ¹H NMR (MeOH-d4) δ: 7.46 (d,J=7.3 Hz, 1H), 7.28-7.36 (m, 4H), 7.21-7.26 (m, 3H), 6.48 (br. s., 1H),4.56 (dd, J=11.2, 8.0 Hz, 1H), 4.03 (s, 2H), 2.92-3.03 (m, 1H),2.73-2.81 (m, 1H), 2.63 (br. s., 1H), 2.20 (m, 1H); MS (m/z) 405.4(M+H⁺).

The following compounds were prepared via coupling of the appropriateamine and acid using the method indicated

MS Ex Name Structure 1H NMR (M + H)⁺ Method  18 (S)-5-benzyl-N-(7-bromo-5-methyl-4- oxo-2,3,4,5- tetrahydrobenzo[b] [1,4]oxazepin-3-yl)isoxazole-3- carboxamide

¹H NMR (DMSO-d₆) δ: 8.88 (d, J = 8.1 Hz, 1H), 7.78 (d, J = 2.3 Hz, 1H),7.46 (dd, J = 8.6, 2.3 Hz, 1H), 7.24-7.40 (m, 5H), 7.19 (d, J = 8.6 Hz,1H), 6.55 (s, 1H), 4.85 (dt, J = 11.7, 7.9 Hz, 1H), 4.54- 4.64 (m, 1H),4.41 (dd, J = 9.9, 7.8 Hz, 1H), 4.22 (s, 2H), 3.30 (s, 3H) 456/458 F  19(S)-N-(7-bromo-5- methyl-4-oxo- 2,3,4,5- tetrahydrobenzo[b][1,4]oxazepin-3-yl)- 3-(4-methylbenzyl)- 1H-pyrazole-5- carboxamide

¹H NMR (DMSO-d₆) δ: 13.18 (s, 1H), 8.09 (d, J = 8.1 Hz, 1H), 7.76 (d, J= 2.3 Hz, 1H), 7.46 (dd, J = 8.6, 2.5 Hz, 1H), 7.19 (d, J = 8.6 Hz, 1H),7.11 (s, 4H), 6.32- 6.36 (m, 1H), 4.79-4.89 (m, 1H), 4.50-4.59 (m, 1H),4.39 (dd, J = 9.7, 7.7 Hz, 1H), 3.93 (s, 2H), 3.30 (s, 3H) 469/471 F  20(S)-3-benzyl-N-(7- bromo-5-methyl-4- oxo-2,3,4,5- tetrahydrobenzo[b][1,4]oxazepin-3-yl)- 1H-pyrazole-5- carboxamide

¹H NMR (CDCl₃) δ: 8.25 (br. s., 1H), 7.24-7.42 (m, 6H), 7.17-7.23 (m,2H), 7.08 (d, J = 8.6 Hz, 1H), 6.55 (s, 1H), 5.14 (dt, J = 11.6, 7.6 Hz,1H), 4.61 (dd, J = 9.7, 7.5 Hz, 1H), 4.31 (dd, J = 11.6, 9.9 Hz, 1H),4.03 (s, 2H), 3.39 (s, 3H) 455/457 F  21 (S)-5-benzyl-N-(8-hydroxy-4-oxo- 2,3,4,5- tetrahydrobenzo[b] [1,4]oxazepin-3-yl)isoxazole-3- carboxamide

¹H NMR (DMSO-d₆) δ: 9.79 (s, 1H), 9.56 (s, 1H), 8.73 (d, J = 8.1 Hz,1H), 7.23-7.41 (m, 5H), 6.91 (d, J = 8.3 Hz, 1H), 6.50-6.61 (m, 3H),4.79 (dt, J = 11.1, 7.3 Hz, 1H), 4.47 (t, J = 10.6 Hz, 1H), 4.38 (dd, J= 10.4, 7.1 Hz, 1H), 4.22 (s, 2H) 380 F  22 (S)-5-benzyl-N-(5-methyl-4-oxo-7-(1H- pyrazol-3-yl)-2,3,4,5- tetrahydrobenzo[b][1,4]oxazepin-3- yl)isoxazole-3- carboxamide

¹H NMR (DMSO-d₆) δ: 12.94 (s, 1H), 8.87 (d, J = 8.3 Hz, 1H), 7.88 (d, J= 2.0 Hz, 1H), 7.81 (d, J = 2.0 Hz, 1H), 7.73 (dd, J = 8.2, 1.9 Hz, 1H),7.20-7.39 (m, 7H), 6.81 (br. m., 1H), 6.55 (s, 1H), 4.84-4.96 (m, 1H),4.54-4.66 (m, 1H), 4.36- 4.47 (m, 1H), 4.22 (s, 2H), 3.36 (s, 3H) 444 F 23 (S)-5-benzyl-N-(5- methyl-4-oxo-7-(1H- pyrazol-1-yl)-2,3,4,5-tetrahydrobenzo[b] [1,4]oxazepin-3- yl)isoxazole-3- carboxamide

¹H NMR (DMSO-d₆) δ: 8.90 (d, J = 8.3 Hz, 1H), 8.58 (d, J = 2.0 Hz, 1H),7.94 (d, J = 2.5 Hz, 1H), 7.73-7.80 (m, 2H), 7.24- 7.39 (m, 6H),6.56-6.60 (m, 1H), 6.55 (s, 1H), 4.91 (dt, J = 11.6, 8.0 Hz, 1H), 4.61(dd, J = 11.6, 10.1 Hz, 1H), 4.44 (dd, J = 9.9, 7.8 Hz, 1H), 4.22 (s,2H), 3.38 (s, 3H) 444 F  24 (S)-5-benzyl-N-(8- bromo-2-oxo-2,3,4,5-tetrahydro-1H- benzo[b]azepin-3- yl)isoxazole-3- carboxamide

¹H NMR (DMSO-d₆) δ: 10.03 (s, 1H), 8.72 (d, J = 7.8 Hz, 1H), 7.25-7.40(m, 7H), 7.21 (d, J = 2.0 Hz, 1H), 6.54 (s, 1H), 4.28- 4.40 (m, 1H),4.21 (s, 2H), 2.61-2.78 (m, 2H), 2.25- 2.38 (m, 2H) 440/442 F  25(S)-N-(8-bromo-2- oxo-2,3,4,5- tetrahydro-1H- benzo[b]azepin-3-yl)-3-(4-methylbenzyl)- 1H-pyrazole-5- carboxamide

¹H NMR (MeOH-d4) δ: 7.36 (dd, J = 8.0, 1.9 Hz, 1H), 7.23-7.31 (m, 2H),7.06-7.16 (m, 4H), 6.45 (s, 1H), 4.55 (dd, J = 11.6, 8.1 Hz, 1H), 3.98(s, 2H), 2.84- 2.96 (m, 1H), 2.74-2.83 (m, 1H), 2.57-2.70 (m, 1H), 2.31(s, 3H), 2.20 (m, 1H) 453/455 F  26 (S)-3-benzyl-N-(8-bromo-2-oxo-2,3,4,5- tetrahydro-1H- benzo[b]azepin-3-yl)- 1H-pyrazole-5-carboxamide

¹H NMR (DMSO-d₆) δ: 13.15 (s, 1H), 10.06 (s, 1H), 7.93 (d, J = 7.6 Hz,1H), 7.16-7.39 (m, 8H), 6.36 (s, 1H), 4.28-4.39 (m, 1H), 3.98 (s, 2H),2.70 (m, 2H), 2.33-2.46 (m, 1H), 2.09- 2.31 (m, 1H) 439/441 F  27(S)-3-(2- fluorobenzyl)-N-(2- oxo-2,3,4,5- tetrahydro-1H-benzo[b]azepin-3-yl)- 1H-pyrazole-5- carboxamide

¹H NMR (MeOH-d4) δ: 7.18-7.36 (m, 6H), 7.04- 7.16 (m, 3H), 6.45 (s, 1H),4.56 (dd, J = 11.6, 8.1 Hz, 1H), 4.07 (s, 2H), 2.91- 3.03 (m, 1H),2.73-2.81 (m, 1H), 2.58-2.67 (m, 1H), 2.13-2.25 (m, 1H) 379 F  28(S)-3-(3- fluorobenzyl)-N-(2- oxo-2,3,4,5- tetrahydro-1H-benzo[b]azepin-3-yl)- 1H-pyrazole-5- carboxamide

¹H NMR (MeOH-d4) δ: 7.28-7.38 (m, 3H), 7.17- 7.25 (m, 1H), 7.03-7.14 (m,2H), 6.98 (d, J = 9.6 Hz, 2H), 6.50 (s, 1H), 4.57 (dd, J = 11.5, 8.0 Hz,1H), 4.06 (s, 2H), 2.90-3.03 (m, 1H), 2.73-2.81 (m, 1H), 2.60- 2.71 (m,1H), 2.15-2.25 (m, 1H) 379 F  29 (S)-1-benzyl-N-(2- oxo-2,3,4,5-tetrahydro-1H- benzo[b]azepin-3-yl)- 1H-1,2,3-triazole-4- carboxamide

¹H NMR (DMSO-d₆) δ: 9.97 (s, 1H), 8.66 (s, 1H), 8.35 (d, J = 7.8 Hz,1H), 7.23-7.45 (m, 7H), 7.11- 7.21 (m, 1H), 7.04 (d, J = 7.8 Hz, 1H),5.65 (s, 2H), 4.37 (dt, J = 11.6, 8.0 Hz, 1H), 2.65-2.85 (m, 2H),2.34-2.46 (m, 1H), 2.18- 2.32 (m, 1H) 362 F  30 (S)-5-benzyl-N-(2-oxo-2,3,4,5- tetrahydro-1H- benzo[b]azepin-3- yl)thiophene-2-carboxamide

¹H NMR (DMSO-d₆) δ: 9.83 (s, 1H), 8.47 (d, J = 8.1 Hz, 1H), 7.72 (d, J =3.8 Hz, 1H), 7.19-7.36 (m, 7H), 7.10-7.18 (m, 1H), 7.03 (d, J = 7.6 Hz,1H), 6.92 (d, J = 3.5 Hz, 1H), 4.34 (m, 1H), 4.14 (s, 2H), 2.72 (m, 2H),2.28 (m, 2H) 377 F  31 (S)-5-benzyl-N-(2- oxo-8-(2-(pyrrolidin-1-yl)ethoxy)-2,3,4,5- tetrahydro-1H- benzo[b]azepin-3- yl)isoxazole-3-carboxamide

¹H NMR (DMSO-d₆) δ: 9.87 (s, 1H), 8.64 (d, J = 7.8 Hz, 1H), 7.26-7.40(m, 5H), 7.19 (d, J = 8.3 Hz, 1H), 6.73 (dd, J = 8.3, 2.8 Hz, 1H), 6.59(d, J = 2.5 Hz, 1H), 6.54 (s, 1H), 4.29- 4.41 (m, 1H), 4.21 (s, 2H),3.96-4.12 (m, 2H), 2.78 (t, J = 5.7 Hz, 2H), 2.60-2.71 (m, 2H), 2.52 (m,4H), 2.21- 2.35 (m, 2H), 1.69 (dt, J = 6.7, 3.2 Hz, 4H) 475 F  325-benzyl-N-((3S)-2- oxo-8- ((tetrahydrofuran-2- yl)methoxy)-2,3,4,5-tetrahydro-1H- benzo[b]azepin-3- yl)isoxazole-3- carboxamide

¹H NMR (DMSO-d₆) δ: 9.87 (s, 1H), 8.64 (d, J = 7.8 Hz, 1H), 7.25-7.40(m, 5H), 7.19 (d, J = 8.3 Hz, 1H), 6.73 (dd, J = 8.3, 2.5 Hz, 1H), 6.60(d, J = 2.5 Hz, 1H), 6.54 (s, 1H), 4.35 (dt, J = 11.2, 8.3 Hz, 1H), 4.21(s, 2H), 4.10-4.18 (m, 1H), 3.83-4.00 (m, 2H), 3.74- 3.83 (m, 1H),3.63-3.72 (m, 1H), 2.65 (dd, J = 9.5, 5.7 Hz, 2H), 2.19-2.36 (m, 2H),1.94-2.05 (m, 1H), 1.77-1.93 (m, 2H), 1.57- 1.73 (m, 1H) 462 F  33(S)-1-(4- methylbenzyl)-N-(2- oxo-2,3,4,5- tetrahydro-1H-benzo[b]azepin-3-yl)- 1H-1,2,3-triazole-4- carboxamide

¹H NMR (MeOH-d4) δ: 8.41 (d, J = 7.1 Hz, 1H), 8.30 (s, 1H), 7.15-7.39(m, 8H), 7.09 (d, J = 7.8 Hz, 1H), 5.55-5.64 (m, 2H), 4.53-4.64 (m, 1H),2.96 (dd, J = 13.4, 8.1 Hz, 1H), 2.73-2.84 (m, 1H), 2.57- 2.71 (m, 1H),2.33 (s, 3H), 2.19-2.29 (m, 1H) 376 F  34 (S)-1-(4- fluorobenzyl)-N-(2-oxo-2,3,4,5- tetrahydro-1H- benzo[b]azepin-3-yl)- 1H-1,2,3-triazole-4-carboxamide

¹H NMR (MeOH-d4) δ: 8.40-8.46 (m, 1H), 8.36 (s, 1H), 7.38-7.45 (m, 2H),7.28-7.36 (m, 2H), 7.19- 7.24 (m, 1H), 7.07-7.17 (m, 3H), 5.64 (s, 2H),4.53- 4.62 (m, 1H), 2.91-3.04 (m, 1H), 2.75-2.82 (m, 1H), 2.65 (m, 1H),2.24 (m, 1H) 380 F  35 (S)-3-benzyl-N-(8- chloro-2-oxo-2,3,4,5-tetrahydro-1H- benzo[b]azepin-3-yl)- 1H-pyrazole-5- carboxamide

¹H NMR (MeOH-d4) δ: 7.27-7.36 (m, 4H), 7.17- 7.27 (m, 4H), 7.13 (d, J =2.0 Hz, 1H), 6.47 (s, 1H), 4.55 (dd, J = 11.5, 8.0 Hz, 1H), 4.03 (s,2H), 2.91 (dd, J = 13.8, 8.0 Hz, 1H), 2.73- 2.85 (m, 1H), 2.59-2.70 (m,1H), 2.21 (m, 1H) 395/397 F  36 (S)-1-benzyl-N-(8- chloro-2-oxo-2,3,4,5-tetrahydro-1H- benzo[b]azepin-3-yl)- 1H-1,2,3-triazole-4- carboxamide

¹H NMR (CDCl₃) δ: 7.95 (s, 2H), 7.55 (s, 1H), 7.36- 7.46 (m, 3H),7.26-7.33 (m, 2H), 7.14-7.26 (m, 2H), 7.06 (d, J = 1.8 Hz, 1H), 5.56 (s,2H), 4.71 (dt, J = 11.2, 7.7 Hz, 1H), 2.91- 3.03 (m, 1H), 2.66-2.85 (m,2H), 2.14 (td, J = 11.8, 7.5 Hz, 1H) 396/398 F  37 (S)-1-benzyl-N-(8-chloro-2-oxo-2,3,4,5- tetrahydro-1H- benzo[b]azepin-3-yl)-1H-imidazole-4- carboxamide

¹H NMR (CDCl₃) δ: 7.92 (d, J = 7.3 Hz, 1H), 7.66 (s, 1H), 7.50-7.60 (m,2H), 7.32-7.46 (m, 3H), 7.19 (m, 4H), 7.05 (s, 1H), 5.14 (s, 2H), 4.70(dt, J = 11.1, 7.7 Hz, 1H), 2.89-3.04 (m, 1H), 2.59-2.86 (m, 2H),2.01-2.20 (m, 1H) 395/397 F  38 (S)-3-benzyl-N-(8- fluoro-2-oxo-2,3,4,5-tetrahydro-1H- benzo[b]azepin-3-yl)- 1H-pyrazole-5- carboxamide

¹H NMR (MeOH-d4) δ: 7.29-7.40 (m, 3H), 7.18- 7.27 (m, 3H), 6.95 (td, J =8.5, 2.7 Hz, 1H), 6.86 (dd, J = 9.5, 2.7 Hz, 1H), 6.49 (br. s., 1H),4.56 (dd, J = 11.6, 8.1 Hz, 1H), 4.03 (s, 2H), 2.90 (td, J = 13.5, 8.0Hz, 1H), 2.78 (dd, J = 13.6, 7.1 Hz, 1H), 2.62 (br. s., 1H), 2.12-2.27(m, 1H) 379 F  39 (S)-1-benzyl-N-(8- fluoro-2-oxo-2,3,4,5-tetrahydro-1H- benzo[b]azepin-3-yl)- 1H-imidazole-4- carboxamide

¹H NMR (MeOH-d4) δ: 7.78 (d, J = 1.3 Hz, 1H), 7.65 (d, J = 1.3 Hz, 1H),7.26-7.42 (m, 6H), 6.95 (td, J = 8.5, 2.5 Hz, 1H), 6.86 (dd, J = 9.6,2.5 Hz, 1H), 5.26 (s, 2H), 4.55 (dd, J = 11.6, 8.1 Hz, 1H), 2.86- 2.97(m, 1H), 2.75-2.83 (m, 1H), 2.57-2.69 (m, 1H), 2.18 (td, J = 12.0, 7.3Hz, 1H) 379 F  40 (S)-5-benzyl-N-(2- oxo-2,3,4,5- tetrahydro-1H-benzo[b]azepin-3-yl)- 4H-1,2,4-triazole-3- carboxamide

¹H NMR (MeOH-d4) δ: 7.18-7.48 (m, 8H), 7.10 (d, J = 7.6 Hz, 1H), 4.58(m, 1H), 4.17 (s, 2H), 2.97 (m 1H), 2.77 (m, 1H), 2.67 (m, 1H), 2.23 (m,1H) 362 F  41 (S)-5-benzyl-N-(8- fluoro-2-oxo-2,3,4,5- tetrahydro-1H-benzo[b]azepin-3-yl)- 4H-1,2,4-triazole-3- carboxamide

¹H NMR (MeOH-d4) δ: 7.22-7.40 (m, 6H), 6.96 (td, J = 8.5, 2.7 Hz, 1H),6.87 (dd, J = 9.6, 2.5 Hz, 1H), 4.58 (dd, J = 11.5, 8.0 Hz, 1H), 4.18(s, 2H), 2.86- 2.98 (m, 1H), 2.75-2.85 (m, 1H), 2.57-2.72 (m, 1H),2.14-2.27 (m, 1H) 380 F  42 (S)-2-benzyl-N-(2- oxo-2,3,4,5-tetrahydro-1H- benzo[b]azepin-3-yl)- 2H-tetrazole-5- carboxamide

¹H NMR (MeOH-d4) δ: 7.36-7.54 (m, 5H), 7.28- 7.36 (m, 2H), 7.17-7.27 (m,1H), 7.10 (d, J = 7.6 Hz, 1H), 5.95 (s, 2H), 4.60 (dd, J = 11.6, 8.1 Hz,1H), 2.98 (td, J = 13.4, 8.1 Hz, 1H), 2.79 (dd, J = 13.3, 6.9 Hz, 1H),2.57-2.72 (m, 1H), 2.24-2.37 (m, 1H) 363 F  43 (S)-2-benzyl-N-(8-fluoro-2-oxo-2,3,4,5- tetrahydro-1H- benzo[b]azepin-3-yl)-2H-tetrazole-5- carboxamide

¹H NMR (MeOH-d4) δ: 7.38-7.47 (m, 5H), 7.34 (dd, J = 8.3, 6.3 Hz, 1H),6.96 (td, J = 8.5, 2.8 Hz, 1H), 6.87 (dd, J = 9.5, 2.7 Hz, 1H), 5.95 (s,2H), 4.61 (dd, J = 11.6, 8.1 Hz, 1H), 2.88-2.99 (m, 1H), 2.76- 2.85 (m,1H), 2.56-2.68 (m, 1H), 2.23-2.36 (m, 1H) 381 F  44 (S)-1-benzyl-N-(1-methyl-2-oxo- 2,3,4,5-tetrahydro- 1H-benzo[b]azepin- 3-yl)-1H-imidazole-4-carboxamide

¹H NMR (MeOH-d4) δ: 7.77 (d, J = 1.3 Hz, 1H), 7.63 (d, J = 1.3 Hz, 1H),7.23-7.44 (m, 9H), 5.25 (s, 2H), 4.51 (dd, J = 11.4, 7.8 Hz, 1H), 3.41(s, 3H), 2.89 (td, J = 13.4, 7.8 Hz, 1H), 2.73 (dd, J = 13.5, 6.7 Hz,1H), 2.54 (tt, J = 13.1, 7.3 Hz, 1H), 2.09-2.20 (m, 1H) 375 F  45(S)-1-benzyl-N-(5- methyl-4-oxo- 2,3,4,5- tetrahydrobenzo[b][1,4]oxazepin-3-yl)- 1H-1,2,4-triazole-3- carboxamide

¹H NMR (MeOH-d4) δ: 8.58 (s, 1H), 7.42-7.48 (m, 1H), 7.28-7.42 (m, 7H),7.20-7.27 (m, 1H), 5.49 (s, 2H), 5.02 (dd, J = 11.4, 7.6 Hz, 1H), 4.61(dd, J = 9.9, 7.6 Hz, 1H), 4.43 (dd, J = 11.4, 9.9 Hz, 1H), 3.42 (s, 3H)378 H  46 (S)-5-benzyl-N-(2- oxo-2,3,4,5- tetrahydro-1H-benzo[b]azepin-3-yl)- 1,3,4-oxadiazole-2- carboxamide

¹H NMR (MeOH-d4) δ: 7.27-7.41 (m, 7H), 7.16- 7.24 (m, 1H), 7.10 (d, J =7.8 Hz, 1H), 4.53 (dd, J = 11.7, 8.2 Hz, 1H), 4.34 (s, 2H), 2.91-3.05(m, 1H), 2.80 (dt, J = 14.0, 7.1 Hz, 1H), 2.52-2.66 (m, 1H), 2.25-2.38(m, 1H) 363 H  47 (S)-5-benzyl-N-(8- fluoro-2-oxo-2,3,4,5-tetrahydro-1H- benzo[b]azepin-3-yl)- 1,3,4-oxadiazole-2- carboxamide

¹H NMR (MeOH-d4) δ: 7.27-7.40 (m, 6H), 6.96 (td, J = 8.5, 2.7 Hz, 1H),6.87 (dd, J = 9.6, 2.5 Hz, 1H), 4.54 (dd, J = 11.9, 8.1 Hz, 1H), 4.34(s, 2H), 2.90 (dd, J = 13.4, 7.8 Hz, 1H), 2.76-2.83 (m, 1H), 2.52- 2.64(m, 1H), 2.26-2.37 (m, 1H) 381 H  48 (S)-1-benzyl-N-(8-fluoro-2-oxo-2,3,4,5- tetrahydro-1H- benzo[b]azepin-3-yl)-1H-1,2,3-triazole-4- carboxamide

¹H NMR (DMSO-d₆) δ: 10.07 (s, 1H), 8.67 (s, 1H), 8.39 (d, J = 7.8 Hz,1H), 7.29-7.42 (m, 6H), 7.00 (td, J = 8.5, 2.7 Hz, 1H), 6.86 (dd, J =9.9, 2.5 Hz, 1H), 5.65 (s, 2H), 4.38 (dt, J = 11.6, 8.0 Hz, 1H), 2.63-2.80 (m, 2H), 2.21-2.47 (m, 2H) 380 H  49 (S)-5-benzyl-N-(1-methyl-2-oxo- 2,3,4,5-tetrahydro- 1H-benzo[b]azepin- 3-yl)-4H-1,2,4-triazole-3- carboxamide

¹H NMR (MeOH-d4) δ: 7.22-7.45 (m, 10H), 4.54 (dd, J = 11.6, 7.8 Hz, 1H),4.14-4.20 (m, 2H), 3.42 (s, 3H), 2.84-2.96 (m, 1H), 2.70-2.78 (m, 1H),2.50- 2.63 (m, 1H), 2.12-2.24 (m, 1H) 376 H  50 (S)-1-benzyl-N-(8-fluoro-1-methyl-2- oxo-2,3,4,5- tetrahydro-1H- benzo[b]azepin-3-yl)-1H-imidazole-4- carboxamide

¹H NMR (MeOH-d4) δ: 7.78 (s, 1H), 7.64 (s, 1H), 7.25-7.44 (m, 6H), 7.19(dd, J = 9.9, 2.5 Hz, 1H), 6.96-7.08 (m, 1H), 5.25 (s, 2H), 4.51 (dd, J= 11.4, 7.8 Hz, 1H), 3.40 (s, 3H), 2.72- 2.91 (m, 2H), 2.45-2.59 (m,1H), 2.07-2.21 (m, 1H) 393 A  51 (S)-1-benzyl-N-(8- fluoro-1-methyl-2-oxo-2,3,4,5- tetrahydro-1H- benzo[b]azepin-3-yl)- 1H-1,2,4-triazole-3-carboxamide

¹H NMR (MeOH-d4) δ: 8.57 (s, 1H), 7.31-7.42 (m, 6H), 7.20 (dd, J = 9.9,2.8 Hz, 1H), 7.03 (td, J = 8.4, 2.7 Hz, 1H), 5.48 (s, 2H), 4.54 (dd, J =11.5, 8.0 Hz, 1H), 3.41 (s, 3H), 2.71- 2.89 (m, 2H), 2.49-2.62 (m, 1H),2.13-2.24 (m, 1H) 394 A  52 (S)-5-benzyl-N-(8- fluoro-1-methyl-2-oxo-2,3,4,5- tetrahydro-1H- benzo[b]azepin-3-yl)- 4H-1,2,4-triazole-3-carboxamide

¹H NMR (MeOH-d4) δ: 7.25-7.39 (m, 6H), 7.20 (dd, J = 9.9, 2.5 Hz, 1H),7.03 (td, J = 8.4, 2.7 Hz, 1H), 4.54 (dd, J = 11.4, 7.8 Hz, 1H), 4.17(s, 2H), 3.41 (s, 3H), 2.71-2.91 (m, 2H), 2.48-2.62 (m, 1H), 2.12- 2.24(m, 1H) 394 A  53 (S)-1-benzyl-N-(1- methyl-2-oxo- 2,3,4,5-tetrahydro-1H-benzo[b]azepin- 3-yl)-1H-1,2,4- triazole-3- carboxamide

¹H NMR (MeOH-d4) δ: 8.57 (s, 1H), 7.32-7.44 (m, 8H), 7.24-7.31 (m, 1H),5.48 (s, 2H), 4.54 (dd, J = 11.4, 7.8 Hz, 1H), 3.42 (s, 3H), 2.83-2.93(m, 1H), 2.68-2.79 (m, 1H), 2.49- 2.63 (m, 1H), 2.12-2.25 (m, 1H) 376 A 54 (S)-5-benzyl-N-(8- chloro-2-oxo-2,3,4,5- tetrahydro-1H-benzo[b]azepin-3-yl)- 4H-1,2,4-triazole-3- carboxamide

¹H NMR (MeOH-d4) δ: 7.24-7.37 (m, 7H), 7.22 (dd, J = 8.1, 2.0 Hz, 1H),7.13 (d, J = 2.0 Hz, 1H), 4.57 (dd, J = 11.6, 8.1 Hz, 1H), 4.17 (s, 2H),2.87- 3.00 (m, 1H), 2.75-2.84 (m, 1H), 2.59-2.70 (m, 1H), 2.16-2.29 (m,1H) 396/398 H  55 (S)-N-(8-chloro-2- oxo-2,3,4,5- tetrahydro-1H-benzo[b]azepin-3-yl)- 5-(4-fluorobenzyl)- 4H-1,2,4-triazole-3-carboxamide

¹H NMR (MeOH-d4) δ: 7.26-7.40 (m, 4H), 7.19- 7.26 (m, 1H), 7.13 (s, 1H),7.01-7.11 (m, 2H), 4.57 (dd, J = 11.4, 8.1 Hz, 1H), 4.16 (s, 2H),2.86-3.01 (m, 1H), 2.75-2.85 (m, 1H), 2.58-2.73 (m, 1H), 2.14- 2.30 (m,1H) 414/416 H  56 (S)-N-(8-chloro-2- oxo-2,3,4,5- tetrahydro-1H-benzo[b]azepin-3-yl)- 5-(3-fluorobenzyl)- 4H-1,2,4-triazole-3-carboxamide

¹H NMR (MeOH-d4) δ: 7.31-7.39 (m, 2H), 7.22 (dd, J = 8.1, 2.3 Hz, 1H),6.96-7.16 (m, 4H), 4.57 (dd, J = 11.6, 8.1 Hz, 1H), 4.19 (s, 2H), 2.93(td, J = 13.3, 8.0 Hz, 1H), 2.80 (dd, J = 13.9, 6.8 Hz, 1H), 2.58- 2.71(m, 1H), 2.19-2.29 (m, 1H) 414/416 H  57 (S)-N-(8-chloro-2- oxo-2,3,4,5-tetrahydro-1H- benzo[b]azepin-3-yl)- 5-(4-methylbenzyl)-4H-1,2,4-triazole-3- carboxamide

¹H NMR (MeOH-d4) δ: 7.33 (d, J = 8.1 Hz, 1H), 7.22 (dd, J = 8.1, 2.0 Hz,1H), 7.12-7.19 (m, 5H), 4.57 (dd, J = 11.6, 8.1 Hz, 1H), 4.12 (s, 2H),2.87- 2.99 (m, 1H), 2.76-2.84 (m, 1H), 2.57-2.71 (m, 1H), 2.32 (s, 3H),2.17-2.28 (m, 1H) 410/412 H  58 (S)-N-(8-fluoro-2- oxo-2,3,4,5-tetrahydro-1H- benzo[b]azepin-3-yl)- 5-(4-fluorobenzyl)-4H-1,2,4-triazole-3- carboxamide

¹H NMR (MeOH-d4) δ: 7.27-7.44 (m, 3H), 7.02- 7.15 (m, 2H), 6.96 (td, J =8.4, 2.4 Hz, 1H), 6.82-6.90 (m, 1H), 4.58 (dd, J = 11.6, 8.1 Hz, 1H),4.16 (s, 2H), 2.86-2.99 (m, 1H), 2.79 (dd, J = 13.6, 7.1 Hz, 1H),2.59-2.73 (m, 1H), 2.13- 2.27 (m, 1H) 398 H  59 (S)-N-(8-fluoro-2-oxo-2,3,4,5- tetrahydro-1H- benzo[b]azepin-3-yl)- 5-(4-methylbenzyl)-4H-1,2,4-triazole-3- carboxamide

¹H NMR (MeOH-d4) δ: 7.34 (dd, J = 8.3, 6.3 Hz, 1H), 7.10-7.23 (m, 6H),6.96 (td, J = 8.5, 2.7 Hz, 1H), 6.87 (dd, J = 9.5, 2.7 Hz, 1H), 4.58(dd, J = 11.6, 8.1 Hz, 1H), 4.12 (s, 2H), 2.92 (td, J = 13.5, 7.8 Hz,1H), 2.79 (dd, J = 13.9, 6.8 Hz, 1H), 2.58-2.70 (m, 1H), 2.32 (s, 3H),2.14-2.26 (m, 1H) 394 H  60 (S)-N-(8-fluoro-2- oxo-2,3,4,5-tetrahydro-1H- benzo[b]azepin-3-yl)- 5-(3-fluorobenzyl)-4H-1,2,4-triazole-3- carboxamide

¹H NMR (MeOH-d4) δ: 7.28-7.41 (m, 2H), 6.93- 7.18 (m, 4H), 6.81-6.92 (m,1H), 4.58 (dd, J = 11.4, 8.1 Hz, 1H), 4.19 (s, 2H), 2.90 (dd, J = 13.3,7.7 Hz, 1H), 2.73-2.85 (m, 1H), 2.58-2.72 (m, 1H), 2.15- 2.29 (m, 1H)398 H  61 (S)-5-benzyl-N-(4- oxo-7- (trifluoromethyl)- 2,3,4,5-tetrahydrobenzo[b] [1,4]oxazepin-3- yl)isoxazole-3- carboxamide

N22077-36-A1: ¹H NMR (DMSO-d₆) δ: 10.36 (s, 1H), 8.92 (d, J = 7.8 Hz,1H), 7.49 (d, J = 2.0 Hz, 1H), 7.44 (dd, J = 8.3, 1.8 Hz, 1H), 7.25-7.38(m, 6H), 6.59 (s, 1H), 4.86 (ddd, J = 9.5, 8.0, 5.6 Hz, 1H), 4.44- 4.57(m, 2H), 4.23 (s, 2H). 431.9 F  62 S)-5-benzyl-N-(7,9- difluoro-2-oxo-2,3,4,5-tetrahydro- 1H-benzo[b]azepin- 3-yl)-4H-1,2,4- triazole-3-carboxamide

1H NMR (DMSO-d6) δ ppm 13.75-15.37 (m, 1H), 9.97 (s, 1H), 8.06-8.97 (m,1H), 6.93-7.69 (m, 6H), 4.24-4.59 (m, 1H), 4.14 (br. s., 2H), 2.68-2.95(m, 2H), 2.32-2.46 (m, 1H), 2.25 (br. s., 1H) 398 H  63(S)-5-benzyl-N-(8- methyl-4-oxo- 2,3,4,5- tetrahydrobenzo[b][1,4]oxazepin-3- yl)isoxazole-3- carboxamide

¹H NMR (DMSO-d₆) δ: 10.01 (s, 1H), 8.79 (d, J = 8.1 Hz, 1H), 7.26-7.39(m, 5H), 6.94-7.02 (m, 3H), 6.57 (s, 1H), 4.75-4.83 (m, 1H), 4.45-4.52(m, 1H), 4.36-4.42 (m, 1H), 4.23 (s, 2H), 2.27 (s, 3H). 377.9 F  64(S)-N-(1-methyl-2- oxo-2,3,4,5- tetrahydro-1H- benzo[b][1,4]diazepin-3-yl)-5-(4- methylbenzyl)-1H- pyrazole-3- carboxamide

¹H NMR (DMSO-d₆, 400 MHz): δ = 13.16 (s, 1 H), 7.91 (d, J = 7.6 Hz, 1H), 7.29 (d, J = 7.6 Hz, 1 H), 6.88-7.20 (m, 8 H), 6.34 (s, 1 H), 5.39(d, J = 5.3 Hz, 1 H), 4.46-4.87 (m, 1 H), 3.93 (s, 2 H), 3.37-3.49 (m, 1H), 2.66-2.76 (m, 3 H), 2.26 ppm (s, 3 H) 390 F  65 (S)-5-benzyl-N-(6-methyl-4-oxo- 2,3,4,5- tetrahydrobenzo[b] [1,4]oxazepin-3-yl)isoxazole-3- carboxamide

¹H NMR (DMSO-d₆) δ: 9.70 (s, 1H), 8.73 (d, J = 8.1 Hz, 1H), 7.24-7.39(m, 5H), 7.01-7.15 (m, 3H), 6.56 (s, 1H), 4.78 (dt, J = 11.4, 8.1 Hz,1H), 4.54 (t, J = 10.7 Hz, 1H), 4.40 (dd, J = 10.1, 8.1 Hz, 1H), 4.22(s, 2H), 2.27 (s, 3H). 377.9 F  66 (S)-5-benzyl-N-(9- methyl-4-oxo-2,3,4,5- tetrahydrobenzo[b] [1,4]oxazepin-3- yl)isoxazole-3- carboxamide

¹H NMR (DMSO-d₆) δ: 10.02 (s, 1H), 8.84 (d, 1H), 7.25-7.39 (m, 5H),7.02- 7.08 (m, 2H), 6.91-6.96 (m, 1H), 6.56 (s, 1H), 4.78 (dt, J = 11.1,7.9 Hz, 1H), 4.44-4.58 (m, 2H), 4.23 (s, 2H), 2.25 (s, 3H). 378.2 F  67(S)-3-(5- benzylisoxazole-3- carboxamido)-5- methyl-N-(2-(methylsulfonyl) ethyl)-4-oxo-2,3,4,5- tetrahydrobenzo[b][1,4]oxazepine-7- carboxamide

¹H NMR (DMSO-d₆) δ: 8.89 (d, J = 8.1 Hz, 1H), 8.84 (t, J = 5.6 Hz, 1H),7.92 (d, J = 2.0 Hz, 1H), 7.75 (dd, J = 8.3, 2.0 Hz, 1H), 7.26-7.38 (m,6H), 6.54 (s, 1H), 4.85 (dt, J = 11.9, 7.8 Hz, 1H), 4.60- 4.68 (m, 1H),4.44 (dd, J = 9.7, 7.7 Hz, 1H), 4.22 (s, 2H), 3.65-3.73 (m, 2H), 3.39(t, J = 6.7 Hz, 2H), 3.34 (s, 3H), 3.05 (s, 3H). 526.9 F  68 (S)-3-(5-benzylisoxazole-3- carboxamido)-5- methyl-4-oxo-N-(2- (pyrrolidin-1-yl)ethyl)-2,3,4,5- tetrahydrobenzo[b] [1,4]oxazepine-7- carboxamide

¹H NMR (DMSO-d₆) δ: 8.88 (d, 1H), 8.52-8.59 (m, 1H), 7.91-7.95 (m, 1H),7.75 (dd, J = 8.3, 2.0 Hz, 1H), 7.25-7.40 (m, 6H), 6.55 (s, 1H), 4.85(dt, J = 11.6, 7.8 Hz, 1H), 4.58- 4.67 (m, 1H), 4.43 (dd, J = 9.9, 7.6Hz, 1H), 4.22 (s, 2H), 3.37-3.46 (m, 2H), 2.56-2.64 (m, 2H), 1.69 (t, J= 3.3 Hz, 4H) 518.0 F  69 (S)-5-benzyl-N-(7- methyl-2-oxo- 1,2,3,4-tetrahydropyrido [2,3-b][1,4] oxazepin-3- yl)isoxazole-3- carboxamide

¹H NMR (DMSO-d₆) δ: 10.18 (s, 1H), 8.89 (d, J = 6.8 Hz, 1H), 7.45 (dd, J= 7.7, 1.4 Hz, 1H), 7.26-7.39 (m, 5H), 7.01-7.07 (m, 1H), 6.59 (s, 1H),4.77- 4.86 (m, 1H), 4.43-4.52 (m, 2H), 4.24 (s, 2H), 2.35 (s, 3H). 379.2F  70 5-(hydroxy(phenyl) methyl)-N-((S)-4- oxo-2,3,4,5-tetrahydrobenzo[b] [1,4]oxazepin-3- yl)thiophene-2- carboxamide

¹H NMR (600 MHz, DMSO-d₆) δ: 10.06 (s, 1 H), 8.62 (d, J = 8.69 Hz, 1 H),7.31-7.37 (m, 2 H), 7.23-7.29 (m, 1 H), 7.08- 7.18 (m, 4 H), 6.87-6.95(m, 1 H), 6.40 (br. s., 1 H), 5.92 (br. s., 1 H), 4.81 (dt, J = 10.39,8.03 Hz, 1 H), 4.45 (td, J = 10.67, 4.72 Hz, 1 H), 4.35-4.42 (m, 1 H).395.1 F  71 (S)-5-benzyl-N-(7- methoxy-4-oxo- 2,3,4,5-tetrahydrobenzo[b] [1,4]oxazepin-3- yl)isoxazole-3- carboxamide

H NMR (DMSO-d₆) δ: 10.06 (s, 1H), 8.85 (d, J = 8.1 Hz, 1H), 7.26-7.39(m, 5H), 7.08 (d, J = 8.8 Hz, 1H), 6.71 (dd, J = 8.8, 3.0 Hz, 1H), 6.67(d, J = 2.8 Hz, 1H), 6.57 (s, 1H), 4.81 (dt, J = 11.2, 7.7 Hz, 1H),4.35- 4.50 (m, 2H), 4.23 (s, 2H), 3.73 (s, 3H). 394.2 F  72(S)-5-benzyl-N-(5- methyl-7- (methylsulfonyl)-4- oxo-2,3,4,5-tetrahydrobenzo[b] [1,4]oxazepin-3- yl)isoxazole-3- carboxamide

¹H NMR (DMSO-d₆) δ: 8.94 (d, J = 8.1 Hz, 1H), 8.04 (d, J = 2.0 Hz, 1H),7.83 (dd, J = 8.3, 2.3 Hz, 1H), 7.48 (d, J = 8.3 Hz, 1H), 7.26-7.38 (m,5H), 6.55 (s, 1H), 4.89 (dt, J = 11.6, 7.8 Hz, 1H), 4.66- 4.72 (m, 1H),4.50 (dd, J = 9.9, 7.6 Hz, 1H), 4.22 (s, 2H), 3.37 (s, 3H), 3.31 (s,3H). [456.1]. 456.1 F  73 (S)-5-benzyl-N-(5- methyl-7- (morpholine-4-carbonyl)-4-oxo- 2,3,4,5- tetrahydrobenzo[b] [1,4]oxazepin-3-yl)isoxazole-3- carboxamide

¹H NMR (CDCl₃) δ: 7.75 (d, J = 7.1 Hz, 1H), 7.31-7.39 (m, 6H), 7.22-7.25(m, 2H), 6.32 (s, 1H), 5.06 (dt, J = 11.2, 7.2 Hz, 1H), 4.75 (dd, J =9.7, 7.2 Hz, 1H), 4.31 (dd, J = 11.1, 10.1 Hz, 1H), 4.13 (s, 2H), 3.75(br. s., 8H), 3.46 (s, 3H). 491.2 F  74 (S)-5-benzyl-N-(4- oxo-2,3,4,5-tetrahydropyrido[4,3- b] [1,4]oxazepin-3- yl)isoxazole-3- carboxamide

¹H NMR (DMSO-d₆) δ: 10.42 (s, 1H), 8.88 (d, J = 7 .6 Hz, 1H), 8.35 (s,1H), 8.12 (d, J = 5.3 Hz, 1H), 7 .24-7.40 (m, 5H), 7.02 (d, J = 5.6 Hz,1H), 6.61 (s, 1H), 4.82 (td, J = 8.0, 3.3 Hz, 1H), 4.40-4.52 (m, 2H),4.24 (s, 2H). 365.2 F  75 (S)-5-benzyl-N-(5,6- dimethyl-4-oxo- 2,3,4,5-tetrahydrobenzo[b] [1,4]oxazepin-3- yl)isoxazole-3- carboxamide

¹H NMR (DMSO-d₆) δ: 8.77 (d, J = 7.8 Hz, 1H), 7.19-7.38 (m, 7H), 7.08(d, J = 7.6 Hz, 1H), 6.55 (s, 1H), 4.74-4.82 (m, 1H), 4.47 (dd, J =11.1, 10.1 Hz, 1H), 4.27 (dd, J = 10.0, 8.0 Hz, 1H), 4.22 (s, 2H), 3.13(s, 3H), 2.32 (s, 3H) 392.1 F  76 (S)-3-(5- benzylisoxazole-3-carboxamido)-N,N,5- trimethyl-4-oxo- 2,3,4,5- tetrahydrobenzo[b][1,4]oxazepine-7- carboxamide

¹H NMR (DMSO-d₆) δ: 8.86 (d, J = 8.1 Hz, 1H), 7.56 (d, J = 2.0 Hz, 1H),7.24-7.39 (m, 7H), 6.55 (s, 1H), 4.88 (dt, J = 11.4, 7.9 Hz, 1H),4.57-4.65 (m, 1H), 4.44 (dd, J = 10.0, 7.7 Hz, 1H), 4.22 (s, 2H), 3.32(s, 3H), 2.98 (d, J = 13.6 Hz, 6H). 449.2 F  77 (S)-5-benzyl-N-(5-methyl-4-oxo- 2,3,4,5- tetrahydrobenzo[b] [1,4]oxazepin-3-yl)isoxazole-3- carboxamide

¹H NMR (DMSO-d₆) δ: 8.85 (d, J = 8.1 Hz, 1H), 7.51 (dd, J = 7.8, 1.8 Hz,1H), 7.25-7.38 (m, 7H), 7.20-7.25 (m, 1H), 6.54 (s, 1H), 4.83 (dt, J =11.6, 8.0 Hz, 1H), 4.58 (dd, J = 11.6, 9.9 Hz, 1H), 4.39 (dd, J = 9.9,7.8 Hz, 1H), 4.22 (s, 2H), 3.30 (s, 3H) 378.3 F  78 (S)-methyl 3-(5-benzylisoxazole-3- carboxamido)-5- methyl-4-oxo- 2,3,4,5-tetrahydrobenzo[b] [1,4]oxazepine-7- carboxylate

¹H NMR (DMSO-d₆) δ: 8.90 (d, J = 7.8 Hz, 1H), 8.01 (d, J = 2.0 Hz, 1H),7.87 (dd, J = 8.3, 2.0 Hz, 1H), 7.27-7.39 (m, 6H), 6.55 (s, 1H), 4.87(dt, J = 11.7, 7.8 Hz, 1H), 4.66 (dd, J = 11.6, 9.9 Hz, 1H), 4.47 (dd, J= 9.9, 7.6 Hz, 1H), 4.22 (s, 2H), 3.88 (s, 3H). 436.4 F  79 S)-5-(cyclopentylmethyl)- N-(5-methyl-7-(5- methyl-1,3,4- oxadiazol-2-yl)-4-oxo-2,3,4,5- tetrahydrobenzo[b] [1,4]oxazepin-3-yl)-4H-1,2,4-triazole-3- carboxamide

¹H NMR (DMSO-d₆, 400 MHz): δ = 8.66 (d, J = 7.8 Hz, 1 H), 7.22-7.44 (m,6 H), 7.07-7.17 (m, 1 H), 6.96-7.06 (m, 2 H), 6.55 (s, 1 H), 5.32 (d, J= 4.5 Hz, 1 H), 4.65 (dt, J = 11.7, 7.0 Hz, 1 H), 4.22 (s, 2 H),3.47-3.69 (m, 2 H), 3.33 ppm (s, 3 H) 452 H  80 (S)-5-benzyl-N-(5-methyl-4-oxo-7-(5- oxo-4,5-dihydro- 1,3,4-oxadiazol-2- yl)-2,3,4,5-tetrahydrobenzo[b] [1,4]oxazepin-3- yl)isoxazole-3- carboxamide

1H NMR (DMSO-d₆) δ 8.33- 8.57 (m, 1H), 8.04 (d, J = 2.0 Hz, 1H), 7.89(dd, J = 8.3, 2.0 Hz, 1H), 7.45 (d, J = 8.3 Hz, 1H), 4.91 (dt, J = 11.6,7.6 Hz, 1H), 4.69 (s, 1H), 4.51 (dd, J = 9.7, 7.5 Hz, 1H), 3.39 (s, 3H),2.72 (d, J = 7.3 Hz, 2H), 2.61 (s, 3H), 2.18-2.31 (m, 1H), 1.40-1.80 (m,5H), 1.07- 1.31 (m, 3H) 462.2 F  81 (S)-5-benzyl-N-(7-fluoro-5-methyl-4- oxo-2,3,4,5- tetrahydrobenzo[b] [1,4]oxazepin-3-yl)-1H-pyrazole-3- carboxamide

¹H NMR (DMSO-d₆) δ: 13.22 (br. s., 1H), 8.11 (br. s., 1H), 7.47 (dd, J =9.9, 2.8 Hz, 1H), 7.19-7.34 (m, 6H), 7.09-7.16 (m, 1H), 6.37 (br. s.,1H), 4.84 (dt, J = 11.5, 8.0 Hz, 1H), 4.47- 4.56 (m, 1H), 4.35-4.42 (m,1H), 3.98 (br. s., 2H), 3.30 (s, 3H). 395.2 F  82 (S)-N-(7-fluoro-5-methyl-4-oxo- 2,3,4,5- tetrahydrobenzo[b] [1,4]oxazepin-3-yl)-5-(4-methylbenzyl)- 1H-pyrazole-3- carboxamide

¹H NMR (DMSO-d₆) δ: 13.18 (br. s., 1H), 8.09 (d, J = 7.8 Hz, 1H), 7.47(dd, J = 9.9, 3.0 Hz, 1H), 7.27 (dd, J = 9.0, 5.7 Hz, 1H), 7.09- 7.15(m, 5H), 6.34 (br. s., 1H), 4.84 (dt, J = 11.4, 8.1 Hz, 1H), 4.46-4.56(m, 1H), 4.35-4.42 (m, 1H), 3.93 (br. s., 2H), 3.30 (s, 3H), 2.26 (s,3H). 409.3 F  83 (S)-1-benzyl-N-(7- fluoro-5-methyl-4- oxo-2,3,4,5-tetrahydrobenzo[b] [1,4]oxazepin-3-yl)- 1H-1,2,3-triazole-4- carboxamide

¹H NMR (DMSO-d₆) δ: 8.69 (s, 1H), 8.61 (d, J = 8.3 Hz, 1H), 7.48 (dd, J= 9.9, 3.0 Hz, 1H), 7.32-7.41 (m, 5H), 7.27 (dd, J = 9.0, 5.7 Hz, 1H),7.13 (td, J = 8.5, 3.0 Hz, 1H), 5.66 (s, 2H), 4.88 (dt, J = 11.6, 7.9Hz, 1H), 4.60 (dd, J = 11.5, 10.0 Hz, 1H), 4.40 (dd, J = 9.9, 7.8 Hz,1H), 3.31 (s, 3H). 396.2 F  84 (S)-1-benzyl-N-(7- fluoro-5-methyl-4-oxo-2,3,4,5- tetrahydrobenzo[b] [1,4]oxazepin-3-yl)- 1H-imidazole-4-carboxamide

¹H NMR (DMSO-d₆) δ: 8.01 (d, J = 7.8 Hz, 1H), 7.90 (d, J = 1.3 Hz, 1H),7.75 (d, J = 1.3 Hz, 1H), 7.46 (dd, J = 9.7, 2.9 Hz, 1H), 7.25-7.39 (m,6H), 7.13 (td, J = 8.5, 2.9 Hz, 1H), 5.23 (s, 2H), 4.83 (dt, J = 11.3,7.9 Hz, 1H), 4.37- 4.50 (m, 2H), 3.31 (s, 3H). 395.3 F  85(S)-5-benzyl-N-(7-(1- (2-cyanoethyl)-1H- tetrazol-5-yl)-5- methyl-4-oxo-2,3,4,5- tetrahydrobenzo[b] [1,4]oxazepin-3-yl)- 1H-pyrazole-3-carboxamide

¹H NMR (DMSO-d₆) δ: 13.23 (br. s., 1H), 8.11 (d, J = 7.6 Hz, 1H), 7.89(d, J = 1.0 Hz, 1H), 7.70 (dd, J = 8.2, 2.1 Hz, 1H), 7.48 (d, J = 8.3Hz, 1H), 7.28-7.34 (m, 2H), 7.19-7.26 (m, 3H), 6.38 (s, 1H), 4.95 (dt, J= 11.6, 7.6 Hz, 1H), 4.74- 4.88 (m, 2H), 4.59-4.67 (m, 1H), 4.48-4.54(m, 1H), 3.99 (s, 2H), 3.37 (s, 3H), 3.24 (t, J = 6.3 Hz, 2H). 498.4 F 86 (S)-1-benzyl-N-(5- methyl-4-oxo-7-(5- oxo-4,5-dihydro-1,3,4-oxadiazol-2- yl)-2,3,4,5- tetrahydrobenzo[b] [1,4]oxazepin-3-yl)-1H-imidazole-4- carboxamide

¹H NMR (DMSO-d₆) δ: 12.66 (br. s., 1H), 8.02 (d, J = 7.8 Hz, 1H), 7.90(d, J = 1.3 Hz, 1H), 7.84 (d, J = 2.0 Hz, 1H), 7.76 (d, J = 1.3 Hz, 1H),7.70 (dd, J = 8.5, 2.1 Hz, 1H), 7.28-7.41 (m, 6H), 5.23 (s, 2H), 4.86(dt, J = 11.6, 7.7 Hz, 1H), 4.53- 4.60 (m, 1H), 4.43-4.49 (m, 1H), 3.36(s, 3H). 377.3 A  87 (S)-5-benzyl-N-(7- fluoro-5-methyl-4- oxo-2,3,4,5-tetrahydrobenzo[b] [1,4]oxazepin-3-yl)- 4H-1,2,4-triazole-3- carboxamide

¹H NMR (DMSO-d₆) δ: 14.38 (br. s., 1H), 8.45 (br. s., 1H), 7.48 (dd, J =9.9, 3.0 Hz, 1H), 7.22-7.36 (m, 6H), 7.14 (td, J = 8.5, 2.9 Hz, 1H),5.76 (s, 1H), 4.81- 4.90 (m, 1H), 4.60 (t, J = 10.5 Hz, 1H), 4.40 (dd, J= 9.7, 7.7 Hz, 1H), 4.13 (br. s., 2H), 3.31 (s, 3H). 396.2 A  88(S)-5-benzyl-N-(6- fluoro-5-methyl-4- oxo-2,3,4,5- tetrahydrobenzo[b][1,4]oxazepin-3- yl)isoxazole-3- carboxamide

¹H NMR (DMSO-d₆) δ: 8.91 (d, J = 7.8 Hz, 1H), 7.26-7.43 (m, 7H), 7.13(d, J = 8.1 Hz, 1H), 6.55 (s, 1H), 4.88 (dt, J = 11.6, 7.9 Hz, 1H), 4.61(dd, J = 11.4, 10.1 Hz, 1H), 4.41 (dd, J = 10.0, 7.7 Hz, 1H), 4.22 (s,2H), 3.22 (d, 2H). 396.3 F  89 (S)-1-benzyl-N-(6- fluoro-5-methyl-4-oxo-2,3,4,5- tetrahydrobenzo[b] [1,4]oxazepin-3-yl)- 1H-imidazole-4-carboxamide

¹H NMR (DMSO-d₆) δ: 8.02 (d, J = 8.1 Hz, 1H), 7.90 (d, J = 1.3 Hz, 1H),7.76 (d, J = 1.3 Hz, 1H), 7.24-7.43 (m, 7H), 7.14 (d, J = 8.3 Hz, 1H),5.24 (s, 2H), 4.87 (dt, J = 11.4, 7.8 Hz, 1H), 4.49-4.57 (m, 1H), 4.40(dd, J = 10.0, 7.7 Hz, 1H), 3.23 (d, 3H). 395.3 F  90 (S)-5-benzyl-N-(6-fluoro-4-oxo-2,3,4,5- tetrahydrobenzo[b] [1,4]oxazepin-3-yl)isoxazole-3- carboxamide

¹H NMR (DMSO-d₆) δ: 10.08 (s, 1H), 8.84 (d, J = 8.1 Hz, 1H), 7.12-7.39(m, 7H), 7.06 (d, 1H), 6.57 (s, 1H), 4.87 (dt, J = 11.3, 7.7 Hz, 1H),4.62 (t, J = 10.7 Hz, 1H), 4.48 (dd, J = 10.2, 7.5 Hz, 1H), 4.21-4.26(m, 2H). 382.3 F  91 (S)-5-benzyl-N-(6- fluoro-5-methyl-4- oxo-2,3,4,5-tetrahydrobenzo[b] [1,4]oxazepin-3-yl)- 4H-1,2,4-triazole-3- carboxamide

¹H NMR (DMSO-d₆) δ: 14.48 (br. s., 1H), 8.52 (br. s., 1H), 7.21-7.45 (m,7H), 7.14 (d, J = 8.1 Hz, 1H), 4.89 (dt, J = 11.5, 7.8 Hz, 1H),4.58-4.70 (m, 1H), 4.41 (dd, J = 9.9, 7.8 Hz, 1H), 4.12 (s, 2H), 3.23(d, J = 2.3 Hz, 3H). 396.3 H  92 (S)-N-(7-fluoro-5- methyl-4-oxo-2,3,4,5- tetrahydrobenzo[b] [1,4]oxazepin-3-yl)- 5-(4-methylbenzyl)-4H-1,2,4-triazole-3- carboxamide

¹H NMR (DMSO-d₆) δ: 14.31 (s, 1H), 8.41 (d, J = 7.3 Hz, 1H), 7.48 (dd, J= 9.9, 3.0 Hz, 1H), 7.28 (dd, J = 9.0, 5.7 Hz, 1H), 7.07- 7.20 (m, 5H),4.85 (dt, J = 11.3, 7.9 Hz, 1H), 4.54- 4.70 (m, 1H), 4.40 (dd, J = 9.9,7.8 Hz, 1H), 4.09 (s, 2H), 3.31 (s, 3H). 410.2 H  93 (S)-N-(6-fluoro-5-methyl-4-oxo- 2,3,4,5- tetrahydrobenzo[b] [1,4]oxazepin-3-yl)-5-(3-fluorobenzyl)- 4H-1,2,4-triazole-3- carboxamide

¹H NMR (DMSO-d₆) δ: 8.50 (br. s., 1H), 7.25-7.44 (m, 3H), 7.06-7.17 (m,4H), 4.89 (dt, J = 11.6, 7.8 Hz, 1H), 4.64 (t, J = 10.7 Hz, 1H), 4.42(dd, J = 9.9, 7.8 Hz, 1H), 4.16 (s, 2H), 3.23 (d, 3H). 414.2 H  94(S)-5-benzyl-N-(4- oxo-2,3,4,5- tetrahydrobenzo[b] [1,4]oxazepin-3-yl)furan-2- carboxamide

¹H NMR (DMSO-d₆) δ: 10.10 (s, 1H), 8.39 (d, J = 8.3 Hz, 1H), 7.30-7.38(m, 2H), 7.22-7.30 (m, 3H), 7.09-7.18 (m, 5H), 6.30 (d, J = 3.3 Hz, 1H),4.76-4.86 (m, 1H), 4.44-4.53 (m, 1H), 4.35-4.42 (m, 1H), 4.06 (s, 2H)363 F  95 (S)-3- (methyl(phenyl) amino)-N-(4-oxo- 2,3,4,5-tetrahydrobenzo[b] [1,4]oxazepin-3- yl)benzamide

¹H NMR (DMSO-d₆) δ: 10.07 (s, 1H), 8.64 (d, J = 8.5 Hz, 1H), 7.27-7.49(m, 5H), 7.09-7.21 (m, 5H), 6.97-7.08 (m, 3H), 4.88 (dt, J = 10.7, 7.7Hz, 1H), 4.47-4.56 (m, 1H), 4.37- 4.45 (m, 1H), 3.30 (s, 3H) 388 F  96(S)-1-(4- fluorobenzyl)-N-(4- oxo-2,3,4,5- tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H- 1,2,3-triazole-4- carboxamide

¹H NMR (DMSO-d₆) δ: 10.15 (s, 1H), 8.73 (s, 1H), 8.60 (d, J = 7.8 Hz,1H), 7.43 (dd, J = 8.4, 5.6 Hz, 2H), 7.23 (t, J = 8.9 Hz, 2H), 7.14 (s,4H), 5.66 (s, 2H), 4.84 (dt, J = 10.5, 7.3 Hz, 1H), 4.49-4.58 (m, 1H),4.39-4.47 (m, 1H) 382 F  97 (S)-N-(5-methyl-4- oxo-2,3,4,5-tetrahydrobenzo[b][1,4] oxazepin-3-yl)-4- phenoxypicolinamide

¹H NMR (CDCl₃) δ: 8.89 (d, J = 7.3 Hz, 1H), 8.43 (d, J = 5.6 Hz, 1H),7.60 (d, J = 2.3 Hz, 1H), 7.34-7.44 (m, 2H), 7.12-7.26 (m, 5H),7.01-7.10 (m, 2H), 6.93 (dd, J = 5.7, 2.7 Hz, 1H), 5.05 (dt, J = 11.3,7.4 Hz, 1H), 4.72 (dd, J = 9.7, 7.5 Hz, 1H), 4.29 (dd, J = 11.1, 9.9 Hz,1H), 3.42 (s, 3H) 390 A  98 (S)-N-(5-methyl-4- oxo-2,3,4,5-tetrahydrobenzo[b] [1,4]oxazep′′′in-3- yl)-3-phenoxy benzamide

¹H NMR (DMSO-d₆) δ: 8.75 (d, J = 8.3 Hz, 1H), 7.66 (d, J = 7.8 Hz, 1H),7.46-7.56 (m, 3H), 7.38- 7.46 (m, 2H), 7.13-7.37 (m, 5H), 7.04 (d, J =8.0 Hz, 2H), 4.91 (dt, J = 11.7, 8.2 Hz, 1H), 4.51-4.60 (m, 1H), 4.40(dd, J = 9.8, 7.8 Hz, 1H), 3.31 (s, 3H) 389 F  99 3-benzyl-N-((S)-4-oxo-2,3,4,5- tetrahydrobenzo[b] [1,4]oxazepin-3- yl)piperidine-1-carboxamide

  (Mixture of diastereomers) ¹H NMR (DMSO-d₆) δ: 9.93 (br. s., 1H),7.02-7.34 (m, 9H), 6.56 (d, J = 8.3 Hz, 1H), 4.54 (dt, J = 10.8, 7.9 Hz,1H), 4.23-4.44 (m, 2H), 3.69-3.93 (m, 2H), 2.64-2.85 (m, 1H), 2.53- 2.60(m, 1H), 2.34-2.48 (m, 2H), 1.51-1.72 (m, 3H), 1.17-1.40 (m, 1H),0.99-1.17 (m, 1H) 380 D 100 (S)-5-(4- chlorobenzyl)-N-(5- methyl-4-oxo-2,3,4,5- tetrahydrobenzo[b] [1,4]oxazepin-3- yl)isoxazole-3- carboxamide

¹H NMR (DMSO-d₆) δ: 8.88 (d, J = 8.3 Hz, 1H), 7.51 (dd, J = 7.7, 1.6 Hz,1H), 7.38-7.45 (m, 2H), 7.19-7.38 (m, 5H), 6.56 (s, 1H), 4.84 (dt, J =11.5, 8.0 Hz, 1H), 4.53-4.63 (m, 1H), 4.40 (dd, J = 9.8, 7.8 Hz, 1H),4.24 (s, 2H), 3.31 (s, 3H) 412 F 101 (S)-1-benzyl-5- methyl-N-(5-methyl-4-oxo-2,3,4,5- tetrahydrobenzo[b] [1,4]oxazepin-3-yl)- 1H-pyrazole-3-carboxamide

¹H NMR (DMSO-d₆) δ: 8.07 (d, J = 8.0 Hz, 1H), 7.50 (dd, J = 7.7, 1.9 Hz,1H), 7.26-7.40 (m, 5H), 7.21-7.26 (m, 1H), 7.13 (d, J = 7.0 Hz, 2H),6.49 (s, 1H), 5.41 (s, 2H), 4.84 (dt, J = 11.5, 7.8 Hz, 1H), 4.50- 4.60(m, 1H), 4.41 (dd, J = 9.7, 7.7 Hz, 1H), 3.32 (s, 3H), 2.22 (s, 3H) 391F 102 (S)-5- (cyclopentylmethyl)- N-(6-fluoro-8- methyl-4-oxo- 2,3,4,5-tetrahydrobenzo[b][1,4] oxazepin-3-yl)-4H- 1,2,4-triazole-3- carboxamide

¹H NMR (DMSO-d₆) δ: 14.17 (br. s., 1H), 10.03 (s, 1H), 8.34 (d, J = 7.5Hz, 1H), 7.00 (d, J = 10.8 Hz, 1H), 6.90 (s, 1H), 4.86 (dt, J = 11.0,7.6 Hz, 1H), 4.60 (t, J = 10.7 Hz, 1H), 4.47 (dd, J = 9.9, 7.4 Hz, 1H),2.74 (d, J = 7.3 Hz, 2H), 2.31 (s, 3H), 2.20-2.30 (m, 1H), 1.46- 1.76(m, 6H), 1.14-1.28 (m, 2H) 388.3 F 103 3-benzyl-N-((S)-5- methyl-4-oxo-2,3,4,5- tetrahydrobenzo[b] [1,4]oxazepin-3- yl)pyrrolidine-1-carboxamide

  Single diastereoisomer. Absolute stereochemistry at the C3 pyrrolidineis unknown. ¹H NMR (CDCl₃) δ: 7.27- 7.34 (m, 4H), 7.15-7.26 (m, 5H),5.24 (d, J = 6.6 Hz, 1H), 4.88 (dt, J = 11.2, 7.0 Hz, 1H), 4.63 (dd, J =9.7, 7.5 Hz, 1H), 4.16 (dd, J = 11.2, 9.7 Hz, 1H), 3.44- 3.55 (m, 2H),3.42 (s, 3H), 3.27-3.36 (m, 1H), 3.01- 3.09 (m, 1H), 2.71 (d, J = 7.6Hz, 2H), 2.44-2.54 (m, 1H), 1.96-2.06 (m, 1H), 1.61-1.71 (m, 1H) 380 D104 3-benzyl-N-((S)-5- methyl-4-oxo- 2,3,4,5- tetrahydrobenzo[b][1,4]oxazepin-3- yl)pyrrolidine-1- carboxamide

  Single diastereoisomer. Absolute stereochemistry at the C3 pyrrolidineis unknown. ¹H NMR (CDCl₃) δ: 7.27- 7.34 (m, 4H), 7.15-7.26 (m, 5H),5.27 (d, J = 6.6 Hz, 1H), 4.87 (dt, J = 11.2, 7.0 Hz, 1H), 4.64 (dd, J =9.7, 7.5 Hz, 1H), 4.17 (dd, J = 11.2, 9.7 Hz, 1H), 3.46-3.57 (m, 2H),3.42 (s, 3H), 3.30 (td, J = 9.1, 7.3 Hz, 1H), 3.04 (dd, J = 9.6, 7.8 Hz,1H), 2.67- 2.74 (m, 2H), 2.43-2.56 (m, 1H), 1.94-2.06 (m, 1H), 1.60-1.72(m, 1H) 380 D 105 N-((S)-5-methyl-4- oxo-2,3,4,5- tetrahydrobenzo[b][1,4]oxazepin-3-yl)- 3-phenoxy pyrrolidine-1- carboxamide

  (Mixture of diastereomers) ¹H NMR (DMSO-d₆) δ: 7.44- 7.50 (m, 1H),7.18-7.33 (m, 5H), 6.90-6.99 (m, 3H), 6.38 (t, J = 8.8 Hz, 1H), 5.03(br. s., 1H), 4.54-4.66 (m, 1H), 4.36-4.45 (m, 1H), 4.30-4.22 (m, 1H),3.37- 3.62 (m, 4H), 3.30 & 3.28 (two s, 3H), 2.03-2.19 (m, 2H) 382 D 106(S)-1-((1H-pyrazol-1- yl)methyl)-5-methyl- N-(5-methyl-4-oxo- 2,3,4,5-tetrahydrobenzo[b] [1,4]oxazepin-3-yl)- 1H-pyrazole-3- carboxamide

¹H NMR (DMSO-d₆) δ: 8.08 (d, J = 8.0 Hz, 1H), 7.98 (d, J = 2.0 Hz, 1H),7.54 (d, J = 1.3 Hz, 1H), 7.50 (dd, J = 7.5, 1.8 Hz, 1H), 7.26-7.36 (m,J = 14.7, 7.4, 7.4, 1.9 Hz, 2H), 7.22-7.26 (m, 1H), 6.41-6.47 (m, 3H),6.30- 6.35 (m, 1H), 4.83 (dt, J = 11.4, 8.0 Hz, 1H), 4.48-4.57 (m, 1H),4.41 (dd, J = 9.9, 7.7 Hz, 1H), 3.32 (s, 3H), 2.46 (s, 3H) 381 F 107(S)-1-benzyl-5- methyl-N-(2-oxo- 2,3,4,5-tetrahydro- 1H-benzo[b]azepin-3-yl)-1H-pyrazole-3- carboxamide

¹H NMR (DMSO-d₆) δ: 10.00 (s, 1H), 7.88 (d, J = 7.8 Hz, 1H), 7.25-7.41(m, 5H), 7.09-7.22 (m, 3H), 7.04 (d, J = 7.5 Hz, 1H), 6.47 (s, 1H), 5.40(s, 2H), 4.34 (dt, J = 11.5, 7.8 Hz, 1H), 2.64-2.85 (m, 2H), 2.37-2.49(m, 1H), 2.13-2.30 (m, 4H) 375 F 108 (S)-3-benzyl-N-(5- methyl-4-oxo-2,3,4,5- tetrahydrobenzo[b] [1,4]oxazepin-3-yl)- 1H-pyrazole-5-carboxamide

¹H NMR (DMSO-d₆) δ: 13.22 (br. s., 1H), 8.11 (br. s., 1H), 7.50 (d, J =7.5 Hz, 1H), 7.18-7.36 (m, 8H), 6.41 (br. s., 1H), 4.83 (dt, J = 11.4,7.8 Hz, 1H), 4.51 (t, J = 10.7 Hz, 1H), 4.35-4.42 (m, 1H), 3.98 (s, 2H),3.31 (s, 3H) 377 F 109 (S)-5-methyl-N-(5- methyl-4-oxo- 2,3,4,5-tetrahydrobenzo[b] [1,4]oxazepin-3-yl)- 1-((2-oxopyridin-1(2H)-yl)methyl)- 1H-pyrazole-3- carboxamide

¹H NMR (DMSO-d₆) δ: 8.07 (d, J = 8.0 Hz, 1H), 7.87 (dd, J = 6.9, 1.6 Hz,1H), 7.44- 7.53 (m, 2H), 7.21-7.36 (m, 3H), 6.40-6.47 (m, 2H), 6.33 (td,J = 6.8, 1.3 Hz, 1H), 6.14 (s, 2H), 4.83 (dt, J = 11.4, 8.0 Hz, 1H),4.46-4.56 (m, 1H), 4.41 (dd, J = 9.8, 7.8 Hz, 1H), 3.32 (s, 3H), 2.47(s, 3H) 408 F 110 (S)-5-methyl-N-(5- methyl-4-oxo- 2,3,4,5-tetrahydrobenzo[b] [1,4]oxazepin-3-yl)- 1-(4-methylbenzyl)-1H-pyrazole-3- carboxamide

¹H NMR (DMSO-d₆) δ: 8.06 (d, J = 8.0 Hz, 1H), 7.50 (dd, J = 7.7, 1.6 Hz,1H), 7.21- 7.37 (m, 3H), 7.17 (d, J = 8.0 Hz, 2H), 7.03 (d, J = 8.0 Hz,2H), 6.47 (s, 1H), 5.35 (s, 2H), 4.84 (dt, J = 11.5, 7.9 Hz, 1H), 4.55(dd, J = 11.4, 9.9 Hz, 1H), 4.41 (dd, J = 9.8, 7.8 Hz, 1H), 3.32 (s,3H), 2.28 (s, 3H), 2.21 (s, 3H) 405 F 111 (S)-1-((3,5-dimethyl-1H-pyrazol-1- yl)methyl)-5-methyl- N-(5-methyl-4-oxo- 2,3,4,5-tetrahydrobenzo[b] [1,4]oxazepin-3-yl)- 1H-pyrazole-3- carboxamide

¹H NMR (DMSO-d₆) δ: 8.01 (d, J = 7.8 Hz, 1H), 7.50 (dd, J = 7.7, 1.9 Hz,1H), 7.22- 7.36 (m, 3H), 6.43 (s, 1H), 6.24 (s, 2H), 5.86 (s, 1H), 4.81(dt, J = 11.3, 7.8 Hz, 1H), 4.37-4.55 (m, 2H), 3.33 (s, 3H), 2.48 (s,6H), 2.07 (s, 3H) 409 F 112 (S)-3-(4- methylbenzyl)-N-(4- oxo-2,3,4,5-tetrahydrobenzo[b] [1,4]oxazepin-3-yl)- 1H-pyrazole-5- carboxamide

¹H NMR (DMSO-d₆) δ: 13.18 (br. s., 1H), 10.13 (s, 1H), 8.10 (br. s.,1H), 7.02- 7.27 (m, 8H), 6.37 (br. s., 1H), 4.72-4.87 (m, 1H), 4.34-4.53(m, 2H), 3.93 (br. s., 2H), 2.27 (s, 3H) 377 F 113 (S)-1-benzyl-5-methyl-N-(4-oxo- 2,3,4,5- tetrahydrobenzo[b] [1,4]oxazepin-3-yl)-1H-pyrazole-3- carboxamide

¹H NMR (DMSO-d₆) δ: 10.15 (s, 1H), 8.09 (d, J = 7.8 Hz, 1H), 7.27-7.42(m, 3H), 7.09-7.19 (m, 6H), 6.52 (s, 1H), 5.41 (s, 2H), 4.81 (dt, J =10.4, 7.2 Hz, 1H), 4.40- 4.53 (m, 2H), 2.23 (s, 3H) 377 F 114(S)-5-methyl-N-(5- methyl-4-oxo- 2,3,4,5- tetrahydrobenzo[b][1,4]oxazepin-3-yl)- 1-(2-methylbenzyl)- 1H-pyrazole-3- carboxamide

¹H NMR (DMSO-d₆) δ: 8.02 (d, J = 8.0 Hz, 1H), 7.49 (dd, J = 7.7, 1.6 Hz,1H), 7.07- 7.38 (m, 6H), 6.53 (s, 1H), 6.40 (d, J = 7.5 Hz, 1H), 5.39(s, 2H), 4.83 (dt, J = 11.5, 7.8 Hz, 1H), 4.46-4.57 (m, 1H), 4.41 (dd, J= 9.9, 7.7 Hz, 1H), 3.31 (s, 3H), 2.35 (s, 3H), 2.19 (s, 3H) 405 F 115(S)-1-(2,5- difluorobenzyl)-5- methyl-N-(5-methyl- 4-oxo-2,3,4,5-tetrahydrobenzo[b] [1,4]oxazepin-3-yl)- 1H-pyrazole-3- carboxamide

¹H NMR (DMSO-d₆) δ: 8.05 (d, J = 8.0 Hz, 1H), 7.50 (dd, J = 7.7, 1.9 Hz,1H), 7.21- 7.38 (m, 5H), 6.76 (ddd, J = 8.8, 5.6, 3.1 Hz, 1H), 6.50 (s,1H), 5.43 (s, 2H), 4.83 (dt, J = 11.4, 8.0 Hz, 1H), 4.48- 4.57 (m, 1H),4.40 (dd, J = 9.8, 7.8 Hz, 1H), 3.31 (s, 3H), 2.28 (s, 3H) 427 F 116(S)-1-benzyl-5- methyl-N-(1-methyl- 2-oxo-2,3,4,5- tetrahydro-1H-benzo[b]azepin-3-yl)- 1H-pyrazole-3- carboxamide

¹H NMR (DMSO-d₆) δ: 7.89 (d, J = 7.8 Hz, 1H), 7.23- 7.42 (m, 7H), 7.12(d, J = 7.0 Hz, 2H), 6.46 (s, 1H), 5.39 (s, 2H), 4.34 (dt, J = 11.5, 7.8Hz, 1H), 3.31 (s, 3H), 2.63- 2.80 (m, 2H), 2.35 (tt, J = 12.8, 7.4 Hz,1H), 2.21 (s, 3H), 2.06-2.20 (m, 1H) 389 F 117 (S)-5-methyl-N-(5-methyl-4-oxo- 2,3,4,5- tetrahydrobenzo[b] [1,4]oxazepin-3-yl)-1-((6-methylpyridin- 3-yl)methyl)-1H- pyrazole-3- carboxamide

¹H NMR (DMSO-d₆) δ: 8.47 (d, J = 1.8 Hz, 1H), 8.07 (d, J = 8.3 Hz, 1H),7.68 (dd, J = 8.3, 2.0 Hz, 1H), 7.44-7.53 (m, 2H), 7.21-7.36 (m, 3H),6.49 (s, 1H), 5.45 (s, 2H), 4.84 (dt, J = 11.4, 7.8 Hz, 1H), 4.53 (dd, J= 11.5, 10.0 Hz, 1H), 4.40 (dd, J = 9.8, 7.8 Hz, 1H), 3.31 (s, 3H), 2.54(s, 3H), 2.28 (s, 3H) 406 F 118 (S)-5-methyl-N-(5- methyl-4-oxo-2,3,4,5- tetrahydrobenzo[b] [1,4]oxazepin-3-yl)- 1-phenethyl-1H-pyrazole-3- carboxamide

¹H NMR (DMSO-d₆) δ: 8.04 (d, J = 8.0 Hz, 1H), 7.51 (dd, J = 7.7, 1.6 Hz,1H), 7.20- 7.37 (m, 6H), 7.13 (d, J = 7.0 Hz, 2H), 6.34 (s, 1H), 4.85(dt, J = 11.4, 8.0 Hz, 1H), 4.51-4.60 (m, 1H), 4.43 (dd, J = 9.7, 7.7Hz, 1H), 4.29 (t, J = 7.2 Hz, 2H), 3.33 (s, 3H), 3.08 (t, J = 7.2 Hz,2H), 1.97 (s, 3H) 405 F 119 5-methyl-N-((S)-5- methyl-4-oxo- 2,3,4,5-tetrahydrobenzo[b] [1,4]oxazepin-3-yl)- 1-(1-phenylethyl)-1H-pyrazole-3- carboxamide

  (Mixture of diasteromers) ¹H NMR (DMSO-d₆) δ: 8.07 (dd, J = 7.9, 2.4Hz, 1H), 7.48-7.54 (m, 1H), 7.23- 7.39 (m, 6H), 7.17 (d, J = 8.0 Hz,2H), 6.46 (s, 1H), 5.68 (q, J = 7.0 Hz, 1H), 4.81- 4.91 (m, 1H), 4.57(ddd, J = 11.4, 9.9, 4.3 Hz, 1H), 4.45 (dd, J = 9.8, 7.8 Hz, 1H), 3.33(s, 3H), 2.17 (s, 3H), 1.85 (dd, J = 6.8, 3.8 Hz, 3H, actually twodoublets from diasteromers) 405 F 120 (S)-5-methyl-N-(5- methyl-4-oxo-2,3,4,5- tetrahydrobenzo[b] [1,4]oxazepin-3-yl)- 1-((2-methylpyrimidin-5- yl)methyl)-1H- pyrazole-3- carboxamide

¹H NMR (DMSO-d₆) δ: 8.60 (s, 2H), 8.08 (d, J = 8.0 Hz, 1H), 7.50 (dd, J= 7.7, 1.9 Hz, 1H), 7.20-7.36 (m, 3H), 6.47 (s, 1H), 5.41 (s, 2H), 4.83(dt, J = 11.5, 7.9 Hz, 1H), 4.54 (dd, J = 11.4, 9.9 Hz, 1H), 4.40 (dd, J= 9.8, 7.8 Hz, 1H), 3.31 (s, 3H), 2.62 (s, 3H), 2.32 (s, 3H) 407 F 121(S)-1-(3,5- difluorobenzyl)-5- methyl-N-(5-methyl- 4-oxo-2,3,4,5-tetrahydrobenzo[b] [1,4]oxazepin-3-yl)- 1H-pyrazole-3- carboxamide

¹H NMR (DMSO-d₆) δ: 8.11 (d, J = 8.0 Hz, 1H), 7.50 (dd, J = 7.8, 1.8 Hz,1H), 7.17- 7.37 (m, 4H), 6.78-6.88 (m, 2H), 6.51 (s, 1H), 5.44 (s, 2H),4.84 (dt, J = 11.5, 7.9 Hz, 1H), 4.55 (dd, J = 11.4, 9.9 Hz, 1H), 4.41(dd, J = 9.8, 7.8 Hz, 1H), 3.32 (s, 3H), 2.24 (s, 3H) 427 v 122(S)-1-(2- fluorobenzyl)-5- methyl-N-(5-methyl- 4-oxo-2,3,4,5-tetrahydrobenzo[b] [1,4]oxazepin-3-yl)- 1H-pyrazole-3- carboxamide

¹H NMR (DMSO-d₆) δ: 8.03 (d, J = 8.0 Hz, 1H), 7.50 (dd, J = 7.7, 1.9 Hz,1H), 7.15- 7.44 (m, 6H), 6.93 (td, J = 7.7, 1.5 Hz, 1H), 6.50 (s, 1H),5.44 (s, 2H), 4.83 (dt, J = 11.5, 7.8 Hz, 1H), 4.48- 4.58 (m, 1H), 4.40(dd, J = 9.8, 7.8 Hz, 1H), 3.31 (s, 3H), 2.26 (s, 3H) 409 F 123(S)-1-(3,4- difluorobenzyl)-5- methyl-N-(5-methyl- 4-oxo-2,3,4,5-tetrahydrobenzo[b] [1,4]oxazepin-3-yl)- 1H-pyrazole-3- carboxamide

¹H NMR (DMSO-d₆) δ: 8.09 (d, J = 8.0 Hz, 1H), 7.39- 7.52 (m, 2H),7.20-7.37 (m, 4H), 6.96 (ddd, J = 6.1, 4.0, 2.0 Hz, 1H), 6.49 (s, 1H),5.40 (s, 2H), 4.84 (dt, J = 11.5, 7.9 Hz, 1H), 4.50-4.59 (m, 1H), 4.41(dd, J = 9.8, 7.8 Hz, 1H), 3.32 (s, 3H), 2.24 (s, 3H) 427 F 124(S)-1-benzyl-N-(1- methyl-2-oxo- 2,3,4,5-tetrahydro- 1H-benzo[b]azepin-3-yl)-1H-pyrazole-4- carboxamide

¹H NMR (DMSO-d₆) δ: 8.28 (s, 1H), 8.25 (d, J = 8.3 Hz, 1H), 7.90 (s,1H), 7.20-7.43 (m, 9H), 5.35 (s, 2H), 4.37 (dt, J = 11.2, 8.4 Hz, 1H),3.29 (s, 3H), 2.66-2.74 (m, 2H), 2.12-2.23 (m, 2H) 375 F 125 (S)-3-(4-fluorobenzyl)-N-(5- methyl-4-oxo- 2,3,4,5- tetrahydrobenzo[b][1,4]oxazepin-3-yl)- 1H-pyrazole-5- carboxamide

¹H NMR (DMSO-d₆) δ: 13.23 (br. s., 1H), 8.09 (br. s., 1H), 7.50 (dd, J =7.5, 1.8 Hz, 1H), 7.20-7.37 (m, 5H), 7.10-7.18 (m, 2H), 6.37 (br. s.,1H), 4.83 (dt, J = 11.3, 8.0 Hz, 1H), 4.50 (t, J = 11.0 Hz, 1H), 4.39(dd, J = 9.7, 7.9 Hz, 1H), 3.98 (br. s., 2H), 3.31 (s, 3H) 395 F 126(S)-1-(2,4- difluorobenzyl)-5- methyl-N-(5-methyl- 4-oxo-2,3,4,5-tetrahydrobenzo[b] [1,4]oxazepin-3-yl)- 1H-pyrazole-3- carboxamide

¹H NMR (DMSO-d₆) δ: 8.02 (d, J = 8.0 Hz, 1H), 7.50 (dd, J = 7.7, 1.6 Hz,1H), 7.20- 7.37 (m, 4H), 7.00-7.15 (m, 2H), 6.49 (s, 1H), 5.40 (s, 2H),4.83 (dt, J = 11.5, 7.8 Hz, 1H), 4.48-4.56 (m, 1H), 4.40 (dd, J = 9.8,7.8 Hz, 1H), 3.31 (s, 3H), 2.27 (s, 3H) 427 F 127 (S)-1-(2-fluorobenzyl)-5- methyl-N-(2-oxo- 2,3,4,5-tetrahydro- 1H-benzo[b]azepin-3-yl)-1H-pyrazole-3- carboxamide

¹H NMR (DMSO-d₆) δ: 9.99 (br. s., 1H), 7.78-7.94 (m, 1H), 7.11-7.48 (m,6H), 6.88-7.10 (m, 2H), 6.50 (br. (s., 1H), 5.43 (br. s., 2H), 4.25-4.42 (m, 1H), 2.64-2.85 (m, 2H), 2.38-2.61 (m, 4H), 2.05-2.22 (m, 1H)393 F 128 (S)-3-(2,4- difluorobenzyl)-N-(5- methyl-4-oxo- 2,3,4,5-tetrahydrobenzo[b] [1,4]oxazepin-3-yl)- 1H-pyrazole-5- carboxamide

¹H NMR (DMSO-d₆) δ: 8.22 (br. s., 1H), 7.50 (dd, J = 7.7, 1.6 Hz, 1H),7.19-7.40 (m, 5H), 7.06 (td, J = 8.5, 1.8 Hz, 1H), 6.41 (br. s., 1H),4.83 (dt, J = 11.5, 8.0 Hz, 1H), 4.51 (t, J = 10.8 Hz, 1H), 4.38 (dd, J= 9.8, 7.8 Hz, 1H), 3.98 (s, 2H), 3.31 (s, 3H) 413 F 129 (S)-1-(2-fluorobenzyl)-N-(5- methyl-4-oxo- 2,3,4,5- tetrahydrobenzo[b][1,4]oxazepin-3-yl)- 1H-pyrazole-4- carboxamide

¹H NMR (DMSO-d₆) δ: 8.37 (d, 1H), 8.30 (s, 1H), 7.91 (s, 1H), 7.52 (dd,J = 7.8, 1.8 Hz, 1H), 7.37-7.45 (m, 1H), 7.18-7.36 (m, 6H), 5.42 (s,2H), 4.89 (dt, J = 11.7, 8.2 Hz, 1H), 4.30-4.48 (m, 2H), 3.30 (s, 3H)395 F 130 (S)-3-benzyl-N-(4- oxo-2,3,4,5- tetrahydrobenzo[b][1,4]oxazepin-3-yl)- 1H-pyrazole-5- carboxamide

¹H NMR (DMSO-d₆) δ: 10.13 (s, 1H), 8.19 (br. s., 1H), 7.10-7.36 (m,10H), 6.44 (br. s., 1H), 4.80 (dt, J = 10.2, 7.4 Hz, 1H), 4.37-4.51 (m,2H), 3.99 (s, 2H) 363 F 131 (S)-N-(5-methyl-4- oxo-2,3,4,5-tetrahydrobenzo[b] [1,4]oxazepin-3-yl)- 1-(4-methylbenzyl)-1H-pyrazole-4- carboxamide

¹H NMR (DMSO-d₆) δ: 8.33 (d, J = 8.8 Hz, 1H), 8.26 (s, 1H), 7.90 (s,1H), 7.51 (d, J = 7.8 Hz, 1H),7.10-7.37 (m, 7H), 5.30 (s, 2H), 4.83-4.94(m, 1H), 4.30-4.49 (m, 2H), 3.30 (s, 3H), 2.29 (s, 3H) 391 F 132(S)-1-benzyl-N-(5- methyl-4-oxo- 2,3,4,5- tetrahydrobenzo[b][1,4]oxazepin-3-yl)- 1H-pyrrole-3- carboxamide

¹H NMR (DMSO-d₆) δ: 7.91- 7.98 (m, 1H), 7.48-7.53 (m, 1H), 7.42 (t, J =1.9 Hz, 1H), 7.19-7.39 (m, 8H), 6.86 (t, J = 2.5 Hz, 1H), 6.51 (dd, J =2.8, 1.8 Hz, 1H), 5.13 (s, 2H), 4.88 (dt, J = 11.9, 8.2 Hz, 1H), 4.46(dd, J = 11.8, 9.8 Hz, 1H), 4.31 (dd, J = 9.8, 7.8 Hz, 1H), 3.30 (s, 3H)773 (2M + Na) F 133 (S)-1-(2,5- difluorobenzyl)-5- methyl-N-(2-oxo-2,3,4,5-tetrahydro- 1H-benzo[b]azepin- 3-yl)-1H-pyrazole-3- carboxamide

¹H NMR (DMSO-d₆) δ: 9.99 (s, 1H), 7.87 (d, J = 7.5 Hz, 1H), 7.21-7.40(m, 4H), 7.13-7.20 (m, 1H), 7.03 (d, J = 7.8 Hz, 1H), 6.77 (ddd, J =8.7, 5.6, 3.3 Hz, 1H), 6.49 (s, 1H), 5.42 (s, 2H), 4.33 (dt, J = 11.5,7.9 Hz, 1H), 2.64- 2.82 (m, 2H), 2.37-2.48 (m, 1H), 2.28 (s, 3H), 2.17(td, J = 12.0, 7.7 Hz, 1H) 411 F 134 (S)-1-benzyl-N-(2- oxo-2,3,4,5-tetrahydro-1H- benzo[b]azepin-3-yl)- 1H-pyrrole-3- carboxamide

¹H NMR (DMSO-d₆) δ: 9.80 (s, 1H), 7.81 (d, J = 8.3 Hz, 1H), 7.20-7.44(m, 8H), 7.11-7.17 (m, 1H), 7.03 (d, J = 7.5 Hz, 1H), 6.84 (t, J = 2.5Hz, 1H), 6.48-6.54 (m, 1H), 5.12 (s, 2H), 4.32-4.46 (m, 1H), 2.64-2.80(m, 2H), 2.24 (td, J = 9.6, 5.6 Hz, 2H) 360 F 135 (S)-3-(4-fluorobenzyl)-N-(4- oxo-2,3,4,5- tetrahydrobenzo[b] [1,4]oxazepin-3-yl)-1H-pyrazole-5- carboxamide

¹H NMR (DMSO-d₆) δ: 13.21 (br. s., 1H), 10.13 (br. s., 1H), 8.11 (d, J =6.3 Hz, 1H), 7.06-7.36 (m, 8H), 6.40 (br. s., 1H), 4.80 (d, J = 8.3 Hz,1H), 4.35-4.53 (m, 2H), 3.99 (br. s., 2H) 381 F 136 (S)-2-(2,5-difluorobenzyl)-N-(5- methyl-4-oxo- 2,3,4,5- tetrahydrobenzo[b][1,4]oxazepin-3-yl)- 2H-tetrazole-5- carboxamide

¹H NMR (DMSO-d₆) δ: 9.15 (d, J = 8.0 Hz, 1H), 7.43- 7.56 (m, 2H),7.22-7.41 (m, 5H), 6.09 (s, 2H), 4.88 (dt, J = 11.5, 7.9 Hz, 1H), 4.66(t, J = 10.7 Hz, 1H), 4.43 (dd, J = 9.5, 8.0 Hz, 1H), 3.32 (s, 3H) 415 F137 (S)-4-butoxy-N-(5- methyl-4-oxo- 2,3,4,5- tetrahydrobenzo[b][1,4]oxazepin-3-yl) picolinamide

¹H NMR (DMSO-d₆) δ: 8.88 (d, J = 8.0 Hz, 1H), 8.49 (d, J = 5.5 Hz, 1H),7.51 (dd, J = 7.5, 1.8 Hz, 1H), 7.45 (d, J = 2.5 Hz, 1H), 7.24-7.38 (m,3H), 7.20 (dd, J = 5.8, 2.8 Hz, 1H), 4.86 (dt, J = 11.2, 7.8 Hz, 1H),4.44-4.60 (m, 2H), 4.12 (t, J = 6.5 Hz, 2H), 3.34 (s, 3H), 1.66-1.78 (m,2H), 1.43 (sxt, J = 7.4 Hz, 2H), 0.93 (t, J = 7.4 Hz, 3H) 370 F 138(S)-4- (cyclopentyloxy)-N- (5-methyl-4-oxo- 2,3,4,5- tetrahydrobenzo[b][1,4]oxazepin-3-yl) picolinamide

¹H NMR (DMSO-d₆) δ: 8.88 (d, J = 8.0 Hz, 1H), 8.48 (d, J = 5.8 Hz, 1H),7.47-7.56 (m, 1H), 7.42 (d, J = 2.5 Hz, 1H), 7.22-7.39 (m, 3H), 7.16(dd, J = 5.5, 2.5 Hz, 1H), 5.00 (t, J = 5.6 Hz, 1H), 4.86 (dt, J = 11.1,8.0 Hz, 1H), 4.39-4.61 (m, 2H), 3.34 (br. s., 3H), 1.86-2.03 (m, 2H),1.51-1.77 (m, 6H) 382 F 139 (S)-2-benzyl-N-(5- methyl-4-oxo- 2,3,4,5-tetrahydrobenzo[b] [1,4]oxazepin-3-yl)- 2H-tetrazole-5- carboxamide

¹H NMR (DMSO-d₆) δ: 9.14 (d, J = 8.0 Hz, 1H), 7.52 (d, J = 7.5 Hz, 1H),7.19-7.45 (m, 8H), 6.03 (s, 2H), 4.87 (dt, J = 11.5, 7.9 Hz, 1H), 4.65(t, J = 10.8 Hz, 1H), 4.42 (dd, J = 9.8, 8.0 Hz, 1H), 3.31 (s, 3H) 379 F140 (S)-1-benzyl-N-(4- oxo-2,3,4,5- tetrahydrobenzo[b][1,4]oxazepin-3-yl)- 1H-imidazole-4- carboxamide

¹H NMR (DMSO-d₆) δ: 10.17 (s, 1H), 8.06 (d, J = 7.8 Hz, 1H), 7.95 (s,1H), 7.80 (s, 1H), 7.25-7.45 (m, 5H), 7.03-7.24 (m, 4H), 5.25 (s, 2H),4.71-4.84 (m, 1H), 4.38-4.48 (m, 2H) 363 F 141 (S)-1-benzyl-N-(2-oxo-2,3,4,5- tetrahydro-1H- benzo[b]azepin-3-yl)- 1H-imidazole-4-carboxamide

¹H NMR (DMSO-d₆) δ: 10.01 (s, 1H), 7.83-7.92 (m, 2H), 7.72 (s, 1H),7.24-7.43 (m, 7H), 7.12-7.20 (m, 1H), 7.03 (d, J = 7.8 Hz, 1H), 5.23 (s,2H), 4.32 (dt, J = 11.4, 7.9 Hz, 1H), 2.65-2.84 (m, 2H), 2.40-2.50 (m,1H), 2.10 (td, 1H) 361 F 142 (S)-N-(5-methyl-4- oxo-2,3,4,5-tetrahydrobenzo[b] [1,4]oxazepin-3-yl)- 1-(4-methylbenzyl)-1H-1,2,3-triazole-4- carboxamide

¹H NMR (DMSO-d₆) δ: 8.66 (s, 1H), 8.57 (d, J = 8.0 Hz, 1H), 7.48-7.54(m, 2H), 7.17-7.36 (m, 6H), 5.60 (s, 2H), 4.86 (dt, J = 11.5, 7.9 Hz,1H), 4.60 (t, J = 10.8 Hz, 1H), 4.40 (dd, J = 9.7, 7.9 Hz, 1H), 3.31 (s,3H), 2.28 (s, 3H) 392 F 143 (S)-1-(4- fluorobenzyl)-N-(5- methyl-4-oxo-2,3,4,5- tetrahydrobenzo[b] [1,4]oxazepin-3-yl)- 1H-1,2,3-triazole-4-carboxamide

¹H NMR (DMSO-d₆) δ: 8.70 (s, 1H), 8.59 (d, J = 8.3 Hz, 1H), 7.51 (dd, J= 7.7, 1.4 Hz, 1H), 7.43 (dd, J = 8.4, 5.6 Hz, 2H), 7.18-7.37 (m, 5H),5.65 (s, 2H), 4.86 (dt, J = 11.5, 8.0 Hz, 1H), 4.61 (t, J = 10.7 Hz,1H), 4.40 (dd, J = 9.7, 7.9 Hz, 1H), 3.32 (s, 3H) 396 F 144 (S)-2-(2,5-difluorobenzyl)-N-(4- oxo-2,3,4,5- tetrahydrobenzo[b][1,4]oxazepin-3-yl)- 2H-tetrazole-5- carboxamide

¹H NMR (DMSO-d₆) δ: 10.17 (s, 1H), 9.15 (d, J = 8.0 Hz, 1H), 7.43-7.51(m, 1H), 7.33-7.41 (m, 2H), 7.09- 7.19 (m, 4H), 6.10 (s, 2H), 4.80-4.90(m, 1H), 4.57 (t, J = 10.7 Hz, 1H), 4.45 (dd, 1H) 401 F 145(S)-2-benzyl-N-(4- oxo-2,3,4,5- tetrahydrobenzo[b] [1,4]oxazepin-3-yl)-2H-tetrazole-5- carboxamide

¹H NMR (DMSO-d₆) δ: 10.17 (s, 1H), 9.14 (d, J = 8.0 Hz, 1H), 7.36-7.46(m, 5H), 7.10-7.18 (m, 4H), 6.05 (s, 2H), 4.86 (dt, J = 10.5, 7.3 Hz,1H), 4.57 (t, J = 10.7 Hz, 1H), 4.45 (dd, 1H) 365 F 146(S)-5-benzyl-N-(5- methyl-4-oxo- 2,3,4,5- tetrahydrobenzo[b][1,4]oxazepin-3-yl)- 1,3,4-oxadiazole-2- carboxamide

¹H NMR (DMSO-d₆) δ: 9.43 (br. s., 1H), 7.52 (dd, J = 7.7, 1.6 Hz, 1H),7.21-7.41 (m, 8H), 4.80 (br. s., 1H), 4.65 (dd, J = 11.6, 9.9 Hz, 1H),4.35-4.45 (m, 3H), 3.31 (s, 3H) 379 F 147 (S)-5-benzyl-N-(4-oxo-2,3,4,5- tetrahydrobenzo[b] [1,4]oxazepin-3-yl)- 1,3,4-oxadiazole-2-carboxamide

¹H NMR (DMSO-d₆) δ: 10.17 (s, 1H), 9.43 (d, J = 8.0 Hz, 1H), 7.28-7.42(m, 5H), 7.11-7.17 (m, 4H), 4.79 (dt, J = 10.5, 7.3 Hz, 1H), 4.56 (t, J= 10.5 Hz, 1H), 4.44 (dd, J = 10.5, 6.5 Hz, 1H), 4.39 (s, 2H) 365 F 148(S)-3-benzyl-N-(4- chloro-5-methyl-6- oxo-6,7,8,9- tetrahydro-5H-pyrimido[4,5-b] [1,4]diazepin-7-yl)- 1H-pyrazole-5- carboxamide

¹H NMR (DMSO-d₆) δ: 13.23 (br. s., 1H), 8.22-8.31 (m, 1H), 8.20 (s, 1H),8.02 (br. s., 1H), 7.29-7.34 (m, 2H), 7.21-7.27 (m, 3H), 6.41 (br. s.,1H), 4.80-4.92 (m, 1H), 3.99 (br. s., 2H), 3.64 (br. s., 1H), 3.39-3.50(m, 1H), 3.17 (s, 3H) 412 F 149 (S)-3-benzyl-N-(4- chloro-6-oxo-6,7,8,9-tetrahydro-5H- pyrimido[4,5-b] [1,4]diazepin-7-yl)- 1H-pyrazole-5-carboxamide

¹H NMR (DMSO-d₆) δ: 13.24 (s, 1H), 9.75 (s, 1H), 8.35 (d, J = 7.0 Hz,1H), 8.10 (s, 1H), 8.05 (d, J = 6.0 Hz, 1H), 7.19-7.37 (m, 5H), 6.43 (s,1H), 4.73 (t, J = 7.5 Hz, 1H), 4.01 (s, 2H), 3.59- 3.69 (m, 1H),3.42-3.53 (m, 1H) 398 F 150 (S)-1-(3- fluorobenzyl)-N-(4- oxo-2,3,4,5-tetrahydrobenzo[b] [1,4]oxazepin-3-yl)- 1H-1,2,3-triazole-4- carboxamide

¹H NMR (DMSO-d₆) δ: 10.14 (s, 1H), 8.76 (s, 1H), 8.60 (d, J = 8.0 Hz,1H), 7.44 (q, J = 7.1 Hz, 1H), 7.06- 7.28 (m, 7H), 5.70 (s, 2H),4.77-4.92 (m, 1H), 4.48- 4.61 (m, 1H), 4.39-4.48 (m, 1H) 382 F 151(S)-5-benzyl-N-(5- methyl-4-oxo- 2,3,4,5- tetrahydrobenzo[b][1,4]oxazepin-3-yl)- 1,2,4-oxadiazole-3- carboxamide

¹H NMR (DMSO-d₆) δ: 9.10 (d, J = 7.8 Hz, 1H), 7.52 (dd, J = 7.8, 1.8 Hz,1H), 7.21- 7.41 (m, 8H), 4.84 (dt, J = 11.4, 7.9 Hz, 1H), 4.62 (dd, J =11.5, 10.0 Hz, 1H), 4.46 (s, 2H), 4.42 (dd, J = 9.9, 7.6 Hz, 1H), 3.31(s, 3H) 379 F 152 (S)-3-benzyl-N-(6- oxo-6,7,8,9- tetrahydro-5H-pyrimido[4,5-b] [1,4]diazepin-7-yl)- 1H-pyrazole-5- carboxamide

¹H NMR (DMSO-d₆) δ: 13.22 (br. s., 1H), 10.25 (s, 1H), 8.20 (s, 1H),8.09 (br. s., 1H), 7.95-8.04 (m, 2H), 7.29-7.35 (m, 2H), 7.20- 7.28 (m,3H), 6.43 (s, 1H), 4.55-4.65 (m, 1H), 4.01 (s, 2H), 3.54-3.63 (m, 1H),3.38-3.48 (m, 1H) 364 F 153 (S)-3-benzyl-N-(5- methyl-6-oxo-6,7,8,9-tetrahydro- 5H-pyrimido[4,5-b] [1,4]diazepin-7-yl)-1H-pyrazole-5- carboxamide

¹H NMR (DMSO-d₆) δ: 9.08 (br. s., 1H), 8.52 (s, 1H), 8.43 (s, 1H), 8.17(br. s., 1H), 7.19- 7.36 (m, 6H), 6.44 (s, 1H), 4.78-4.89 (m, 1H), 4.00(s, 2H), 3.55-3.70 (m, 2H), 3.33 (s, 3H) 378 F 154 (S)-1-benzyl-N-(5-methyl-6-oxo- 6,7,8,9-tetrahydro- 5H-pyrimido[4,5-b][1,4]diazepin-7-yl)- 1H-1,2,4-triazole-3- carboxamide

¹H NMR (DMSO-d₆) δ: 9.10 (br. s., 1H), 8.87 (s, 1H), 8.52 (s, 1H),8.42-8.49 (m, 2H), 7.30-7.43 (m, 5H), 5.51 (s, 2H), 4.82-4.89 (m, 1H),3.58-3.71 (m, 2H), 3.34 (s, 3H) 379 F 155 (S)-5-benzyl-N-(4-oxo-2,3,4,5- tetrahydrobenzo[b] [1,4]oxazepin-3-yl)- 1,2,4-oxadiazole-3-carboxamide

¹H NMR (DMSO-d₆) δ: 10.17 (s, 1H), 9.07 (d, J = 8.0 Hz, 1H), 7.08-7.46(m, 9H), 4.76-4.89 (m, 1H), 4.37- 4.61 (m, 4H) 365 F 156 (S)-5-(difluoro(phenyl) methyl)-N-(4-oxo- 2,3,4,5- tetrahydrobenzo[b][1,4]oxazepin-3- yl)isoxazole-3- carboxamide

¹H NMR (400 MHz, CDCl₃) δ ppm 4.34 (t, 1 H) 4.79 (dd, J = 10.36, 6.57Hz, 1 H) 5.09 (dt, J = 10.55, 6.60 Hz, 1 H) 6.87 (s, 1 H) 7.05-7.10 (m,1 H) 7.13-7.23 (m, 3 H) 7.45-7.68 (m, 5 H) 7.83 (d, J = 6.82 Hz, 1 H)8.26 (s, 1 H) 400 A 157 (S)-5- (difluoro(phenyl) methyl)-N-(5-methyl-4-oxo-2,3,4,5- tetrahydrobenzo[b] [1,4]oxazepin-3- yl)isoxazole-3-carboxamide

¹H NMR (400 MHz, CDCl₃) δ ppm 3.46 (s, 3 H) 4.28 (dd, J = 11.12, 9.85Hz, 1 H) 4.76 (dd, J = 9.85, 7.33 Hz, 1 H) 5.04 (dt, J = 11.12, 7.07 Hz,1 H) 6.83 (s, 1 H) 7.18-7.32 (m, 5 H) 7.45-7.56 (m, 3 H) 7.56-7.64 (m, 2H) 7.83 (d, J = 6.82 Hz, 1 H) 414 A 158 (S)-5-(3- bromobenzyl)-N-(5-methyl-4-oxo- 2,3,4,5- tetrahydrobenzo[b] [1,4]oxazepin-3-yl)-1H-pyrazole-3- carboxamide

1H NMR (400 MHz, CDCl₃) δ ppm 3.34 (s, 3 H) 3.91 (s, 2 H) 4.21 (dd, J =11.37, 9.85 Hz, 1 H) 4.59 (dd, J = 9.85, 7.58 Hz, 1 H) 5.06 (dt, J =11.49, 7.64 Hz, 1 H) 6.43 (s, 1 H) 7.00-7.21 (m, 6 H) 7.21-7.32 (m, 2 H)8.07 (d, J = 7.58 Hz, 1 H) 12.45 (br. s., 1 H) 455 A 159 (S)-5-(4-bromobenzyl)-N-(5- methyl-4-oxo- 2,3,4,5- tetrahydrobenzo[b][1,4]oxazepin-3-yl)- 1H-pyrazole-3- carboxamide

¹H NMR (400 Hz, DMSO- d6) δ ppm 3.31 (s, 3 H) 3.97 (s, 2 H) 4.39 (dd, J= 9.60, 7.83 Hz, 1 H) 4.52 (t, J = 10.74 Hz, 1 H) 4.83 (d, J = 11.62 Hz,1 H) 6.38 (s, 1 H) 7.09-7.40 (m, 5 H) 7.43- 7.62 (m, 3 H) 8.08 (d, J =8.08 Hz, 1 H) 13.22 (s, 1 H) 455 A 160 5-benzyl-N-(7-bromo-2-oxo-2,3,4,5- tetrahydro-1H- benzo[b]azepin-3- yl)isoxazole-3-carboxamide

1H NMR (400 MHz, CDCl₃) δ ppm 2.02-2.75 (m, 2 H) 2.77-3.09 (m, 2 H) 4.12(s, 2 H) 4.66 (dt, J = 11.18, 7.67 Hz, 1 H) 6.34 (s, 1 H) 6.91 (d, J =8.34 Hz, 1 H) 7.23- 7.39 (m, 5 H) 7.39-7.49 (m, 3 H) 7.68 (d, J = 6.82Hz, 1 H) 442 F

Example 161(S)-5-benzyl-N-(7-chloro-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-3-yl)-4H-1,2,4-triazole-3-carboxamide

Preparation 1: The title compound was prepared via coupling of theappropriate amine and acid using Method H.

Preparation 2: To a solution of(S)-3-amino-4,5-dihydro-1H-benzo[b]azepin-2(3H)-one (50 g, 284 mmol),5-benzyl-4H-1,2,4-triazole-3-carboxylic acid (72.1 g, 355 mmol) indichloromethane (1500 ml) was added DIPEA (173 ml, 993 mmol) at 15° C.The reaction mixture was stirred for 20 minutes and2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane 2,4,6-trioxide (236 ml,397 mmol) was slowly added at 15° C. The reaction was stirred for overnight. The resulting solid was filtered and the solid was washed withDCM. The solid was dried under vacuum at 50° C. for over night. For thefiltration, it was concentrated under rotary-evaporator and to thesticky residue added plenty of cold water and stirring, the slowlyprecipitated white solid was collected and washed the solid with waterand ethyl ether. The solid was dried under vacuum at 50° C. for 3 daysto afford the product(S)-5-benzyl-N-(2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-3-yl)-4H-1,2,4-triazole-3-carboxamide(Total recovery: 102 g, 282 mmol, 99% yield). ¹H NMR (MeOH-d4) δ:7.18-7.48 (m, 8H), 7.10 (d, J=7.6 Hz, 1H), 4.58 (m, 1H), 4.17 (s, 2H),2.97 (m 1H), 2.77 (m, 1H), 2.67 (m, 1H), 2.23 (m, 1H). MS (m/z) 362(M+H⁺).

To a solution of(S)-5-benzyl-N-(2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-3-yl)-4H-1,2,4-triazole-3-carboxamide(35 g, 97 mmol) in DMA (700 ml) was added NCS (14.87 g, 111 mmol) at 0°C. After 30 mins, the reaction mixture was warmed up to RT and continuedstirring for 5 hrs. A second portion of NCS (3.88 g, 29.1 mmol) wasadded to the reaction mixture and stirring continued for an additional24 hrs. A third portion of NCS (1.293 g, 9.68 mmol) was then added andthe solution was stirred at RT for 16 h further. The reaction was thenquenched with cold water. The white solid was collected by filtrationand washed with water 3 times to provide(S)-5-benzyl-N-(7-chloro-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-3-yl)-4H-1,2,4-triazole-3-carboxamide(36 g, 91 mmol, 94% yield). The product was air dried overnight.Additional purification was achieved by suspending(S)-5-benzyl-N-(7-chloro-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-3-yl)-4H-1,2,4-triazole-3-carboxamide(10 g, 25.3 mmol) in hot methanol (500 mL) for 1 h. The solution wasthen cooled to RT, filtered and the solid was washed with methanol 2times (75 mL) to give the product (7 g, 70% yield). ¹H NMR (DMSO-d₆) δ:10.06 (s, 1H), 8.31 (br. s., 1H), 7.44 (d, J=2.5 Hz, 1H), 7.18-7.40 (m,7H), 7.05 (d, J=8.6 Hz, 1H), 4.32 (dt, J=11.5, 7.9 Hz, 1H), 4.11 (s,2H), 2.63-2.80 (m, 2H), 2.37-2.49 (m, 1H), 2.25 (br. s., 1H). MS (m/z)396/398 (M+H⁺).

The following compounds were prepared via coupling of the appropriateamine and acid using the method indicated.

162 (S)-5-benzyl-N-(7- bromo-2-oxo-2,3,4,5- tetrahydro-1H-benzo[b]azepin-3-yl)- 1H-pyrazole-3- carboxamide

1H NMR (400 MHz, MeOD- d4) δ ppm 2.17 (m, 1 H) 2.65 (m, 1 H) 2.72-2.81(m, 1 H) 2.86-3.00 (m, 1 H) 4.03 (s, 2 H) 4.55 (dd, J = 11.62, 8.08 Hz,1 H) 6.47 (s, 1 H) 7.01 (d, J = 8.34 Hz, 1 H) 7.23 (d, J = 7.58 Hz, 3 H)7.30 (d, J = 6.82 Hz, 2 H) 7.46 (dd, J = 8.46, 2.15 Hz, 1 H) 7.53 (d, J= 2.27 Hz, 1 H) 440   F 163 (S)-5-benzyl-N-(7- bromo-2-oxo-2,3,4,5-tetrahydro-1H- benzo[b]azepin-3-yl)- 4H-1,2,4-triazole-3- carboxamide

1H NMR (400 MHz, DMSO- d6) δ ppm 2.66-2.80 (m, 2 H) 3.39 (m, 2 H) 4.12(br. s., 2 H) 4.24-4.42 (m, 1 H) 6.99 (d, J = 8.34 Hz, 1 H) 7.16- 7.41(m, 5 H) 7.47 (dd, J = 8.34, 2.27 Hz, 1 H) 7.57 (d, J = 2.27 Hz, 1 H)10.06 (s, 1 H) 442   H 164 (S)-5-benzyl-N-(6- fluoro-8-methyl-4-oxo-2,3,4,5- tetrahydrobenzo[b] [1,4]oxazepin-3-yl)- 4H-1,2,4-triazole-3-carboxamide

¹H NMR (DMSO-d₆) δ: 14.38 (br. s., 1H), 10.02 (s, 1H), 8.42 (br. s.,1H), 7.21- 7.38 (m, 5H), 7.00 (d, J = 10.8 Hz, 1H), 6.90 (s, 1H), 4.85(dt, J = 11.1, 7.6 Hz, 1H), 4.57-4.68 (m, 1H), 4.45 (dd, J = 9.9, 7.4Hz, 1H), 4.13 (br. s., 2H), 2.30 (s, 3H) 396.2 F 165 (S)-5-benzyl-N-(7-cyano-2-oxo-2,3,4,5- tetrahydro-1H- benzo[b]azepin-3-yl)-4H-1,2,4-triazole-3- carboxamide

1H NMR (400 MHz, DMSO- d6) δ ppm 2.34 (m, 2 H) 2.62- 2.87 (m, 2 H) 4.12(br. s., 2 H) 4.23-4.48 (m, 1 H) 7.19 (d, J = 8.34 Hz, 1 H) 7.21- 7.39(m, 5 H) 7.75 (dd, J = 8.21, 1.89 Hz, 1 H) 7.83 (d, J = 1.77 Hz, 1 H)8.30 (br. s., 1 H) 10.38 (s, 1 H) 387   F 166 (S)-5-benzyl-N-(2-oxo-7-(1H-tetrazol-5- yl)-2,3,4,5- tetrahydro-1H- benzo[b]azepin-3-yl)-4H-1,2,4-triazole-3- carboxamide

¹H NMR (400 MHz, DMSO- d6) δ ppm 2.20-2.39 (m, 1 H) 2.44 (m, 1 H)2.75-2.85 (m, 2 H) 4.11 (s, 2 H) 4.39 (dt, J = 11.37, 7.83 Hz, 1 H) 7.12(d, J = 8.34 Hz, 1 H) 7.20- 7.38 (m, 5 H) 7.91 (dd, J = 8.21, 1.89 Hz, 1H) 7.97 (d, J = 1.52 Hz, 1 H) 8.32 (br. s., 1 H) 10.12 (s, 1 H) 430   F1 167 (S)-5-benzyl-N-(2- oxo-7-(1H-pyrazol-4- yl)-2,3,4,5-tetrahydro-1H- benzo[b]azepin-3-yl)- 4H-1,2,4-triazole-3- carboxamide

1H NMR (400 MHz, DMSO- d6) δ ppm 1.42 (d, J = 7.83 Hz, 1 H) 1.80-1.96(m, 1 H) 1.97-2.11 (m, 1 H) 2.11- 2.27 (m, 1 H) 3.35 (s, 2 H) 3.82 (dd,J = 11.49, 7.96 Hz, 1 H) 6.29 (d, J = 8.08 Hz, 1 H) 6.38-6.59 (m, 5 H)6.65- 6.82 (m, 2 H) 7.19 (br. s., 2 H) 428   F 168 5-benzyl-N-(1-methyl-2-oxo-7- (2,2,2-trifluoro-1,1- dihydroxyethyl)-2,3,4,5-tetrahydro- 1H-benzo[b]azepin- 3-yl)-1H-pyrazole-3- carboxamide

1H NMR (400 MHz, CDCl₃) δ ppm 2.11 (m, 2 H) 2.51- 2.70 (m, 2 H) 3.44 (s,3 H) 4.00 (s, 2 H) 4.68 (dt, J = 11.56, 7.86 Hz, 1 H) 6.50 (s, 1 H)7.14-7.32 (m, 6 H) 7.37 (d, J = 8.34 Hz, 1 H) 7.96 (s, 1 H) 8.05 (d, J =8.34 Hz, 1 H) 8.22 (d, J = 7.83 Hz, 1 H) 489   F 169 (S)-5-benzyl-N-(5-methyl-7-(5-methyl- 1,3,4-oxadiazol-2- yl)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4] oxazepin-3-yl)-4H- 1,2,4-triazole-3- carboxamide

¹H NMR (DMSO-d₆) δ: 14.38 (br. s., 1H), 8.45 (br. s., 1H), 8.04 (d, J =1.5 Hz, 1H), 7.88 (dd, J = 8.3, 1.8 Hz, 1H), 7.45 (d, J = 8.5 Hz, 1H),7.23-7.37 (m, 5H), 4.91 (dt, J = 11.5, 7.8 Hz, 1H), 4.62- 4.81 (m, 1H),4.49 (dd, J = 9.4, 7.9 Hz, 1H), 4.14 (br. s., 2H), 3.39 (s, 3H), 2.61(s, 3H) 460.2 F 170 (S)-1-benzyl-N-(7- bromo-2-oxo-2,3,4,5-tetrahydro-1H- benzo[b]azepin-3-yl)- 1H-1,2,4-triazole-3- carboxamide

1H NMR (400 MHz, DMSO- d6) δ ppm 2.22 (t, J = 11.62 Hz, 1 H) 2.37-2.48(m, 1 H) 2.63-2.79 (m, 2 H) 4.32 (dt, J = 11.43, 7.80 Hz, 1 H) 5.48 (s,2 H) 6.99 (d, J = 8.34 Hz, 1 H) 7.27-7.42 (m, 5 H) 7.47 (dd, J = 8.46,2.40 Hz, 1 H) 7.57 (d, J = 2.27 Hz, 1 H) 8.29 (d, J = 7.58 Hz, 1 H) 8.82(s, 1 H) 10.07 (s, 1 H) 442   F 171 N-[(3S)-7-deuterio- 1-methyl-2-oxo-2,3,4,5-tetrahydro- 1H-1-benzazepin-3- yl]-5-(phenylmethyl)-1H-pyrazole-3- carboxamide

1H NMR (400 MHz, MeOD- d4) δ ppm 2.10-2.21 (m, 1 H) 2.54 (br. s., 1 H)2.68- 2.81 (m, 1 H) 2.86 (dd, J = 13.26, 7.96 Hz, 1 H) 3.41 (s, 3 H)4.02 (s, 2 H) 4.52 (dd, J = 11.62, 7.83 Hz, 1 H) 6.45 (br. s., 1 H) 7.23(d, J = 7.33 Hz, 3 H) 7.26-7.35 (m, 4 H) 7.35-7.44 (m, 2 H) 376   A 172(R)-5-benzyl-N-(4- oxo-2,3,4,5- tetrahydrobenzo[b] [1,4]thiazepin-3-yl)isoxazole-3- carboxamide

1H NMR (CDCl₃) δ: 7.80 (br. s., 1H), 7.70 (dd, J = 7.7, 1.4 Hz, 1H),7.49-7.60 (m, 1H), 7.18-7.48 (m, 5H), 7.14 (dd, J = 7.8, 1.3 Hz, 1H),6.33 (s, 1H), 4.86 (dt, J = 11.7, 7.0 Hz, 1H), 4.13 (s, 2H), 3.98 (dd, J= 11.1, 6.6 Hz, 1H), 3.04 (t, J = 11.4 Hz, 1H) 380   A 173(S)-3-butoxy-N-(4- oxo-2,3,4,5- tetrahydrobenzo[b] [1,4]oxazepin-3-yl)benzamide

1H NMR (DMSO-d6) δ: 10.08 (br. s., 1H), 8.67 (d, J = 8.0 Hz, 1H), 7.42(d, J = 4.5 Hz, 4H), 7.16 (br. s., 6H), 4.90 (d, J = 8.0 Hz, 1H),4.33-4.67 (m, 2H), 4.02 (br. s., 2H), 1.72 (d, J = 5.0 Hz, 2H),1.30-1.56 (m, 2H), 0.77- 1.06 (m, 3H) 355   F 174 (S)-5-(4-methoxybenzyl)-N- (4-oxo-2,3,4,5- tetrahydrobenzo[b] [1,4]oxazepin-3-yl)thiophene-2- carboxamide

¹H NMR (DMSO-d₆) δ: 10.07 (s, 1H), 8.52-8.69 (m, 1H), 7.69 (d, J = 3.8Hz, 1H), 7.05-7.28 (m, 6H), 6.78- 7.01 (m, 3H), 4.67-4.94 (m, 1H), 4.46(s, 2H), 4.08 (s, 2H), 3.72 (s, 3H) 409   F 175 (R)-N-(5-methyl-4-oxo-2,3,4,5- tetrahydrobenzo[b][1,4] thiazepin-3-yl)-3- phenoxybenzamide

¹H NMR (DMSO-d₆) δ: 8.91 (d, J = 7.8 Hz, 1H), 7.56- 7.75 (m, 4H),6.92-7.55 (m, 8H), 4.58 (dt, J = 12.1, 7.4 Hz, 1H), 3.52 (dd, J = 11.4,7.1 Hz, 2H), 3.29 (s, 3H) 405   A 176 (S)-N-(5-methyl-4- oxo-2,3,4,5-tetrahydrobenzo[b] [1,4]oxazepin-3-yl)- 5-(4-methylbenzyl)-1H-pyrazole-3- carboxamide

¹H NMR (DMSO-d₆) δ: 13.18 (br. s., 1H), 8.40-8.72 (m, 1H), 8.05 (d, J =7.8 Hz, 1H), 7.50 (dd, J = 7.6, 1.8 Hz, 1H), 7.01-7.40 (m, 6H), 6.34(br. s., 1H), 5.76 (s, 1H), 4.72-5.01 (m, 1H), 4.25- 4.68 (m, 2H), 3.93(br. s., 3H), 2.26 (s, 3H) 391   A 177 (S)-N-(5-methyl-4- oxo-2,3,4,5-tetrahydrobenzo[b] [1,4]oxazepin-3-yl)- 5-pentyl-1H- pyrazole-3-carboxamide

¹H NMR (DMSO-d₆) 13.04 (s, 1H), 8.06 (d, J = 8.0 Hz, 1H), 7.50 (dd, J =7.7, 1.6 Hz, 1H), 7.08-7.41 (m, 3H), 6.38 (d, J = 1.5 Hz, 1H), 4.71-4.97 (m, 1H), 4.28-4.64 (m, 2H), 2.49-2.56 (m, 3H), 1.46-1.80 (m, 2H),1.12- 1.43 (m, 6H), 0.86 (t, J = 6.9 Hz, 3H) 357   F 178(S)-1-(2-iodobenzyl)- N-(5-methyl-4-oxo- 2,3,4,5- tetrahydrobenzo[b][1,4]oxazepin-3-yl)- 1H-pyrazole-3- carboxamide

¹H NMR (DMSO-d₆) 8.15 (d, J = 8.0 Hz, 1H), 7.82-8.01 (m, 2H), 7.51 (dd,J = 7.7, 1.6 Hz, 1H), 7.19-7.45 (m, 4H), 7.11 (td, J = 7.7, 1.5 Hz, 1H),6.65-6.83 (m, 2H), 5.45 (s, 2H), 4.85 (dt, J = 11.5, 7.9 Hz, 1H), 4.55(dd, J = 11.5, 10.0 Hz, 1H), 4.40 (dd, J = 9.8, 7.8 Hz, 1H), 3.16-3.40(m, 3H) 503   F 179 (S)-3-(4- methoxyphenethyl)- N-(5-methyl-4-oxo-2,3,4,5- tetrahydrobenzo[b] [1,4]oxazepin-3- yl)isoxazole-5- carboxamide

¹H NMR (DMSO-d₆) δ: 9.14 (d, J = 8.0 Hz, 1H), 7.53 (dd, J = 7.8, 1.8 Hz,1H), 6.96- 7.41 (m, 5H), 6.75-6.97 (m, 3H), 4.83 (dt, J = 11.5, 8.0 Hz,1H), 4.31-4.68 (m, 2H), 3.64-3.78 (m, 3H), 3.31 (s, 3H), 2.83-3.07 (m,4H) 422   F 180 (S)-5-isobutyl-N-(5- methyl-4-oxo- 2,3,4,5-tetrahydrobenzo[b] [1,4]oxazepin-3- yl)isoxazole-3- carboxamide

¹H NMR (DMSO-d₆) δ: 8.86 (d, J = 8.1 Hz, 1H), 7.52 (dd, J = 7.7, 1.6 Hz,1H), 7.10- 7.44 (m, 3H), 6.58 (s, 1H), 4.85 (dt, J = 11.6, 8.0 Hz, 1H),4.61 (dd, J = 11.6, 9.9 Hz, 1H), 4.41 (dd, J = 9.7, 7.7 Hz, 1H), 3.31(s, 3H), 2.71 (d, J = 7.1 Hz, 2H), 2.00 (dt, J = 13.5, 6.8 Hz, 1H), 0.91(d, 6H) 344   F 181 (S)-5-isobutyl-N-(5- methyl-4-oxo- 2,3,4,5-tetrahydrobenzo[b] [1,4]oxazepin-3-yl)- 1H-pyrazole-3- carboxamide

¹H NMR (DMSO-d₆) 13.04 (br. s., 1H), 8.09 (br. s., 1H), 7.51 (dd, J =7.7, 1.9 Hz, 1H), 7.09-7.43 (m, 3H), 6.39 (br. s., 1H), 4.84 (dt, J =11.5, 7.9 Hz, 1H), 4.27-4.65 (m, 2H), 2.48 (d, J = 7.0 Hz, 3H), 1.88(dt, J = 13.6, 6.8 Hz, 2H), 1.09-1.41 (m, 1H), 0.67-1.06 (m, 6H) 343   F182 (S)-N-(5-methyl-4- oxo-2,3,4,5- tetrahydrobenzo[b][1,4]oxazepin-3-yl)- 5-propyl-1H- pyrazole-3- carboxamide

¹H NMR (DMSO-d₆) 8.11 (d, J = 8.0 Hz, 1H), 7.51 (dd, J = 7.7, 1.9 Hz,1H), 7.16-7.44 (m, 3H), 6.42 (s, 1H), 4.84 (dt, J = 11.5, 7.9 Hz, 1H),4.25-4.67 (m, 2H), 3.32 (s, 3H), 2.58 (t, J = 7.4 Hz, 2H), 1.51-1.69 (m,2H), 1.20- 1.30 (m, 0H), 0.88 (t, J = 7.3 Hz, 3H) 329   F 183(S)-1-benzyl-N-(5- methyl-4-oxo- 2,3,4,5- tetrahydrobenzo[b][1,4]oxazepin-3-yl)- 1H-pyrazole-4- carboxamide

¹H NMR (DMSO-d₆) 8.17- 8.45 (m, 2H), 7.92 (s, 1H), 7.52 (dd, J = 7.8,1.8 Hz, 1H), 7.14-7.43 (m, 9H), 5.28-5.47 (m, 2H), 4.89 (dt, J = 11.7,8.3 Hz, 1H), 4.24- 4.57 (m, 2H), 3.40 (br. s., 3H) 377   F 184(S)-3-(allyloxy)-N- (5-methyl-4-oxo- 2,3,4,5- tetrahydrobenzo[b][1,4]oxazepin-3- yl)benzamide

¹H NMR (DMSO-d₆) 8.66 (d, J = 8.3 Hz, 1H), 6.94- 7.65 (m, 8H), 5.93-6.21(m, J = 17.3, 10.5, 5.2, 5.2 Hz, 1H), 5.42 (dd, J = 17.2, 1.6 Hz, 1H),5.28 (dd, J = 10.5, 1.5 Hz, 1H), 4.93 (dt, J = 11.7, 8.1 Hz, 1H),4.51-4.73 (m, 3H), 4.41 (dd, J = 9.8, 7.8 Hz, 1H), 3.32 (s, 3H) 353   F185 (S)-3-butoxy-N-(5- methyl-4-oxo- 2,3,4,5- tetrahydrobenzo[b][1,4]oxazepin-3- yl)benzamide

¹H NMR (DMSO-d₆) 8.65 (d, J = 8.5 Hz, 1H), 7.53 (dd, J = 7.8, 1.8 Hz,1H), 7.19-7.47 (m, 5H), 7.05-7.17 (m, 1H), 6.97 (s, 1H), 4.93 (dt, J =11.8, 8.2 Hz, 1H), 4.58 (dd, J = 11.8, 10.0 Hz, 1H), 4.41 (dd, J = 9.9,7.9 Hz, 1H), 4.02 (t, J = 6.4 Hz, 2H), 3.32 (s, 3H), 1.61-1.82 (m, 2H),1.34-1.60 (m, 2H), 0.95 (t, J = 7.4 Hz, 3H) 367   F 186(S)-N-(5-methyl-4- oxo-2,3,4,5- tetrahydrobenzo[b] [1,4]oxazepin-3-yl)-6-phenoxy picolinamide

1H NMR (DMSO-d6) 8.42 (d, J = 7.6 Hz, 1H), 7.94- 8.11 (m, 1H), 7.73 (d,J = 6.8 Hz, 1H), 7.42-7.61 (m, 3H), 7.20-7.39 (m, 5H), 7.13 (d, J = 8.1Hz, 1H), 4.81 (dt, J = 11.4, 7.6 Hz, 1H), 4.49 (dd, J = 9.9, 7.6 Hz,1H), 4.37 (dd, J = 11.4, 10.1 Hz, 1H), 3.33- 3.39 (m, 3H) 390   F 187(S)-N-(5-methyl-4- oxo-2,3,4,5- tetrahydrobenzo[b] [1,4]oxazepin-3-yl)-3-phenethyl-1H- pyrazole-5- carboxamide

1H NMR (DMSO-d6) 13.09 (br. s., 1H), 8.06 (br. s., 1H), 7.50 (dd, J =7.7, 1.6 Hz, 1H), 7.07-7.39 (m, 8H), 6.38 (br. s., 1H), 4.83 (dt, J =11.2, 7.9 Hz, 1H), 4.25-4.62 (m, 2H), 3.35 (s, 3H), 2.92 (s, 4H) 391   A188 (S)-N-(2-oxo-2,3,4,5- tetrahydro-1H- benzo[b]azepin-3-yl)-3-phenethyl-1H- pyrazole-5- carboxamide

1H NMR (DMSO-d6) 13.09 (br. s., 1H), 8.06 (br. s., 1H), 7.50 (dd, J =7.7, 1.6 Hz, 1H), 7.07-7.39 (m, 8H), 6.38 (br. s., 1H), 4.83 (dt, J =11.2, 7.9 Hz, 1H), 4.25-4.62 (m, 2H), 2.92 (s, 4H), 2.81- 2..91 (m, 2H)375   A 189 (S)-1-methyl-N-(5- methyl-4-oxo- 2,3,4,5- tetrahydrobenzo[b][1,4]oxazepin-3-yl)- 5-(phenoxymethyl)- 1H-pyrazole-3- carboxamide

¹H NMR (DMSO-d₆) 8.11 (d, J = 8.1 Hz, 1H), 6.89-7.61 (m, 9H), 6.76 (s,1H), 5.21 (s, 2H), 4.84 (dt, J = 11.6, 7.9 Hz, 1H), 4.32-4.66 (m, 2H),3.93 (s, 3H), 3.32 (d, J = 4.0 Hz, 2H) 407   F 190 (S)-5-benzyl-N-(1-methyl-2-oxo- 2,3,4,5-tetrahydro- 1H-benzo[b] [1,4]diazepin-3-yl)-1H-pyrazole-3- carboxamide

¹H NMR (DMSO-d₆) 13.19 (s, 1H), 7.91 (d, J = 7.3 Hz, 1H), 6.91-7.46 (m,9H), 6.37 (s, 1H), 5.38 (d, J = 5.6 Hz, 1H), 4.64 (d, J = 6.6 Hz, 1H),3.85-4.20 (m, 3H), 3.65 (d, J = 1.0 Hz, 1H), 3.36- 3.56 (m, 1H), 3.33(s, 3H) 376   F 191 (S)-5-(2- fluorobenzyl)-N-(1- methyl-2-oxo-2,3,4,5-tetrahydro- 1H-benzo[b]azepin- 3-yl)-1H-pyrazole-3- carboxamide

¹H NMR (DMSO-d₆) 13.19 (br. s., 1H), 7.91 (br. s., 1H), 6.83-7.68 (m,7H), 6.29 (br. s., 1H), 4.22-4.47 (m, 1H), 3.86-4.20 (m, 2H), 3.33 (s,3H), 2.57-2.87 (m, 2H), 2.14 (br. s., 2H) 393   A 192 (S)-5-(2-fluorobenzyl)-N-(5- methyl-4-oxo- 2,3,4,5- tetrahydrobenzo[b][1,4]oxazepin-3-yl)- 1H-pyrazole-3- carboxamide

¹H NMR (DMSO-d₆) 13.27 (br. s., 1H), 8.43-8.79 (m, 1H), 8.09 (br. s.,1H), 7.49 (d, J = 7.3 Hz, 1H), 7.01- 7.41 (m, 6H), 6.32 (br. s., 1H),4.75-4.97 (m, 1H), 4.25-4.66 (m, 2H), 4.01 (br. s., 2H), 3.34 (s, 3H)395   A 193 (S)-5-benzyl-N-(5- oxo-3,4,5,6- tetrahydro-2H- benzo[b][1,4]oxazocin-4- yl)isoxazole-3- carboxamide

¹H NMR (CDCl₃) 7.90 (d, J = 6.8 Hz, 1H), 7.79 (s, 1H), 7.07-7.47 (m,7H), 6.32 (s, 1H), 5.32 (s, 1H), 4.56-4.88 (m, 2H), 3.93-4.25 (m, 3H),2.26-2.48 (m, 1H), 1.98- 2.20 (m, 1H) 378   A 194 (S)-5-((methyl(phenyl) amino)methyl)-N-(5- methyl-4-oxo- 2,3,4,5-tetrahydrobenzo[b] [1,4]oxazepin-3-yl)- 1H-pyrazole-3- carboxamide

¹H NMR (DMSO-d₆) 13.27 (br. s., 1H), 7.85-8.22 (m, 1H), 6.42-7.68 (m,9H), 6.36 (br. s., 1H), 4.83 (br. s., 1H), 4.28-4.74 (m, 4H), 3.17-3.42(m, 3H), 2.69 (s, 3H) 406   A 195 (S)-1-benzyl-N-(5- methyl-4-oxo-2,3,4,5- tetrahydrobenzo[b] [1,4]oxazepin-3-yl)- 1H-1,2,3-triazole-4-carboxamide

1H NMR (DMSO-d6) δ: 8.69 (s, 1H), 8.57 (d, J = 8.1 Hz, 1H), 7.51 (dd, J= 7.7, 1.6 Hz, 1H), 7.17-7.43 (m, 8H), 5.66 (s, 2H), 4.86 (d, J = 11.6Hz, 1H), 4.60 (dd, J = 11.6, 10.1 Hz, 1H), 4.40 (dd, J = 9.9, 7.6 Hz,1H), 3.22-3.40 (m, 3H) 378   A 196 (S)-N-(5-methyl-4- oxo-2,3,4,5-tetrahydrobenzo[b] [1,4]oxazepin-3-yl)- 5-(thiophen-2- ylmethyl)-4H-1,2,4-triazole-3- carboxamide

¹H NMR (DMSO-d₆) δ: 14.42 (br. s., 1H), 8.42 (d, J = 7.8 Hz, 1H), 7.51(d, J = 7.8 Hz, 1H), 7.22-7.45 (m, 4H), 6.93-7.02 (m, 2H), 4.78- 4.88(m, 1H), 4.59 (t, J = 10.5 Hz, 1H), 4.24-4.47 (m, 3H), 3.32 (s, 3H)384.1 F 197 (S)-5-(2- fluorobenzyl)-N-(4- oxo-2,3,4,5-tetrahydrobenzo[b] [1,4]oxazepin-3-yl)- 1H-pyrazole-3- carboxamide

¹H NMR (DMSO-d₆) 13.26 (br. s., 1H), 10.12 (br. s., 1H), 8.11 (br. s.,1H), 6.96- 7.48 (m, 9H), 6.34 (br. s., 1H), 4.78 (br. s., 1H), 4.29-4.63 (m, 2H), 4.02 (br. s., 2H) 381   A 198 (S)-2-benzyl-N-(5-methyl-4-oxo- 2,3,4,5- tetrahydrobenzo[b] [1,4]oxazepin-3- yl)oxazole-4-carboxamide

¹H NMR (DMSO-d₆) 8.56 (s, 1H), 8.24 (d, J = 8.1 Hz, 1H), 7.50 (dd, J =7.7, 1.9 Hz, 1H), 7.12-7.43 (m, 8H), 4.83 (dt, J = 11.6, 7.9 Hz, 1H),4.57 (dd, J = 11.5, 10.0 Hz, 1H), 4.40 (dd, J = 9.9, 7.8 Hz, 1H), 4.22(s, 2H), 3.20-3.38 (m, 3H) 378   A 199 5-methyl-N-((S)-5- methyl-4-oxo-2,3,4,5- tetrahydrobenzo[b] [1,4]oxazepin-3-yl)- 1-((tetrahydrofuran-2-yl)methyl)-1H- pyrazole-3- carboxamide

¹H NMR (CDCl₃) 8.58 (d, J = 8.1 Hz, 1H), 7.77 (d, J = 7.1 Hz, 1H),6.98-7.39 (m, 3H), 6.47 (d, J = 8.1 Hz, 1H), 4.97- 5.40 (m, 1H),4.51-4.85 (m, 1H), 3.94-4.47 (m, 3H), 3.64-3.94 (m, 1H), 3.44 (d, J =1.3 Hz, 3H), 2.21-2.42 (m, 3H), 2.05 (s, 2H), 1.63- _ 1.95 (m, 2H),1.18-1.41 (m, 2H) 385   A 200 (S)-1-benzyl-N-(5- methyl-4-oxo- 2,3,4,5-tetrahydrobenzo[b] [1,4]oxazepin-3-yl)- 1H-imidazole-4- carboxamide

1H NMR (DMSO-d6) 6: 7.98 (d, J = 8.1 Hz, 1H), 7.89 (d, J = 1.3 Hz, 1H),7.75 (d, J = 1.0 Hz, 1H), 7.49 (dd, J = 7.6, 1.8 Hz, 1H), 7.16-7.42 (m,7H), 5.23 (s, 2H), 4.81 (dt, J = 11.2, 7.9 Hz, 1H), 4.27- 4.60 (m, 2H),3.22-3.43 (m, 3H) 377   A 201 (S)-5-(3- fluorobenzyl)-N-(5-methyl-4-oxo- 2,3,4,5- tetrahydrobenzo[b] [1,4]oxazepin-3-yl)-1H-pyrazole-3- carboxamide

¹H NMR (DMSO-d₆) 13.23 (br. s., 1H), 8.08 (d, J = 7.8 Hz, 1H), 7.50 (d,J = 7.6 Hz, 1H), 7.16-7.43 (m, 4H), 6.91-7.16 (m, 3H), 6.41 (s, 1H),4.72-4.97 (m, 1H), 4.27-4.63 (m, 2H), 4.01 (s, 2H), 3.15-3.43 (m, 3H)395   A 202 (S)-5-(3- fluorobenzyl)-N-(4- oxo-2,3,4,5-tetrahydrobenzo[b] [1,4]oxazepin-3-yl)- 1H-pyrazole-3- carboxamide

¹H NMR (DMSO-d₆) 13.22 (s, 1H), 10.13 (s, 1H), 8.10 (d, J = 7.6 Hz, 1H),7.24- 7.58 (m, 2H), 6.94-7.22 (m, 6H), 6.43 (s, 1H), 4.71-4.94 (m, 1H),4.37-4.54 (m, 2H), 4.02 (s, 2H) 381   A 203 (S)-5-benzyl-N-(5-methyl-4-oxo- 2,3,4,5- tetrahydrobenzo[b] [1,4]oxazepin-3-yl)thiophene-2- carboxamide

1H NMR (DMSO-d6) δ: 8.60 (d, J = 8.3 Hz, 1H), 7.71 (d, J = 3.8 Hz, 1H),7.50 (dd, J = 7.7, 1.6 Hz, 1H), 7.15-7.38 (m, 8H), 6.95 (d, J = 3.8 Hz,1H), 4.84 (dt, J = 11.7, 8.1 Hz, 1H), 4.50 (dd, J = 11.7, 10.0 Hz, 1H),4.37 (dd, J = 9.9, 7.8 Hz, 1H), 4.15 (s, 2H), 3.30 (s, 3H) 393   A 204(S)-1-(3- fluorobenzyl)-N-(5- methyl-4-oxo- 2,3,4,5- tetrahydrobenzo[b][1,4]oxazepin-3-yl)- 1H-imidazole-4- carboxamide

1H NMR (400 MHz, DMSO- d6) δ 9.37 (none, 1H), 7.99 (d, J = 7.83 Hz, 1H),7.91 (d, J = 1.26 Hz, 1H), 7.79 (d, J = 1.01 Hz, 1H), 7.00-7.59 (m, 8H),5.25 (s, 2H), 4.81 (dt, J = 8.02, 11.24 Hz, 1H), 4.32- 4.57 (m, 2H),3.32 (d, J = 4.29 Hz, 3H) 395   A 205 (S)-1-(3- fluorobenzyl)-N-(2-oxo-2,3,4,5- tetrahydro-1H- benzo[b]azepin-3-yl)- 1H-imidazole-4-carboxamide

¹H NMR (DMSO-d₆) 9.83 (s, 1H), 8.44 (d, J = 8.3 Hz, 1H), 7.89-8.13 (m,1H), 7.77 (s, 1H), 6.69-7.57 (m, 7H), 5.76 (s, 1H), 5.50 (s, 2H),4.23-4.50 (m, 1H), 2.61- 2.84 (m, 2H), 2.13-2.37 (m, 2H) 379   A 206(S)-N-(5-methyl-4- oxo-2,3,4,5- tetrahydrobenzo[b] [1,4]oxazepin-3-yl)-1-(4-methylbenzyl)- 1H-imidazole-4- carboxamide

¹H NMR (DMSO-d₆) 7.97 (d, J = 7.8 Hz, 1H), 7.87 (d, J = 1.0 Hz, 1H),7.72 (d, J = 1.3 Hz, 1H), 7.49 (dd, J = 7.6, 1.8 Hz, 1H), 6.97-7.41 (m,6H), 5.76 (s, 1H), 5.17 (s, 2H), 4.81 (dt, J = 11.2, 7.9 Hz, 1H),4.21-4.59 (m, 2H), 3.34 (s, 3H), 2.27 (s, 3H) 391   A 207 (S)-5-(4-methylbenzyl)-N-(4- oxo-2,3,4,5- tetrahydrobenzo[b] [1,4]oxazepin-3-yl)-4H-1,2,4-triazole-3- carboxamide

¹H NMR (DMSO-d₆) 13.95- 14.91 (m, 1H), 10.16 (s, 1H), 8.51 (br. s., 1H),7.08-7.52 (m, 7H), 4.80 (dt, J = 10.5, 7.1 Hz, 1H), 4.35-4.64 (m, 2H),4.12 (s, 2H), 2.51 (s, 3H) 364   A 208 (S)-N-(5-methyl-4- oxo-2,3,4,5-tetrahydrobenzo[b] [1,4]oxazepin-3-yl)- 5-(4-methylbenzyl)-4H-1,2,4-triazole-3- carboxamide

¹H NMR (DMSO-d₆) 14.13- 14.72 (m, 1H), 8.31-8.77 (m, 1H), 6.82-7.66 (m,8H), 4.83 (dt, J = 11.6, 7.9 Hz, 1H), 4.29-4.72 (m, 2H), 4.06 (s, 2H),3.10-3.45 (m, 3H), 2.27 (s, 3H) 392   A 209 (S)-5-(4-fluorobenzyl)-N-(5- methyl-4-oxo- 2,3,4,5- tetrahydrobenzo[b][1,4]oxazepin-3-yl)- 4H-1,2,4-triazole-3- carboxamide

¹H NMR (DMSO-d₆) 14.08- 14.88 (m, 1H), 8.48 (br. s., 1H), 6.84-7.75 (m,8H), 4.83 (dt, J = 11.6, 7.9 Hz, 1H), 4.60 (t, J = 10.7 Hz, 1H), 4.41(dd, J = 9.9, 7.8 Hz, 1H), 4.12 (s, 2H), 3.00- 3.47 (m, 3H) 396   A 210(S)-5-(3- fluorobenzyl)-N-(5- methyl-4-oxo- 2,3,4,5- tetrahydrobenzo[b][1,4]oxazepin-3-yl)- 4H-1,2,4-triazole-3- carboxamide

¹H NMR (DMSO-d₆) 14.09- 14.89 (m, 1H), 8.50 (br. s., 1H), 6.75-7.62 (m,8H), 4.83 (dt, J = 11.4, 7.8 Hz, 1H), 4.60 (t, J = 10.6 Hz, 1H), 4.41(dd, J = 9.7, 7.7 Hz, 1H), 4.16 (s, 2H), 3.32 (s, 3H) 396   A 211(S)-1-(3- fluorobenzyl)-N-(5- methyl-4-oxo- 2,3,4,5- tetrahydrobenzo[b][1,4]oxazepin-3-yl)- 1H-1,2,3-triazole-4- carboxamide

¹H NMR (DMSO-d₆) 8.72 (s, 1H), 8.58 (d, J = 8.1 Hz, 1H), 7.07-7.65 (m,8H), 5.68 (s, 2H), 4.87 (d, J = 11.6 Hz, 1H), 4.60 (dd, J = 11.6, 9.9Hz, 1H), 4.40 (dd, J = 9.9, 7.8 Hz, 1H), 3.21-3.41 (m, 3H) 396   A 212(S)-5-benzyl-N-(7- chloro-5-methyl-4- oxo-2,3,4,5- tetrahydrobenzo[b][1,4]oxazepin-3-yl)- 4H-1,2,4-triazole-3- carboxamide

1H NMR (400 MHz, DMSO- d6) δ 13.93-15.01 (m, 1H), 8.22-8.73 (m, 1H),7.66 (d, J = 2.53 Hz, 1H), 7.06-7.45 (m, 6H), 4.74-5.11 (m, 1H),4.54-4.70 (m, 1H), 4.42 (dd, J = 7.58, 9.85 Hz, 1H), 3.14- 3.46 (m, 3H)412   A 213 (S)-1-benzyl-N-(7- chloro-5-methyl-4- oxo-2,3,4,5-tetrahydrobenzo[b] [1,4]oxazepin-3-yl)- 1H-imidazole-4- carboxamide

¹H NMR (DMSO-d₆) 8.00 (d, J = 8.1 Hz, 1H), 7.90 (d, J = 1.3 Hz, 1H),7.76 (d, J = 1.3 Hz, 1H), 7.64 (d, J = 2.5 Hz, 1H), 7.14-7.51 (m, 7H),5.23 (s, 2H), 4.83 (dt, J = 11.4, 7.8 Hz, 1H), 4.28-4.64 (m, 2H),3.26-3.39 (m, 3H) 411   A 214 (S)-1-benzyl-N-(7- chloro-5-methyl-4-oxo-2,3,4,5- tetrahydrobenzo[b] [1,4]oxazepin-3-yl)-1H-1,2,3-triazole-4- carboxamide

¹H NMR (DMSO-d₆) 8.70 (s, 1H), 8.60 (d, J = 8.1 Hz, 1H), 7.66 (d, J =2.3 Hz, 1H), 7.10- 7.52 (m, 6H), 5.66 (s, 2H), 4.88 (dt, J = 11.6, 8.0Hz, 1H), 4.62 (dd, J = 11.5, 10.0 Hz, 1H), 4.41 (dd, J = 9.7, 7.7 Hz,1H), 3.22-3.40 (m, 3H) 412   A 215 (S)-5-benzyl-N-(7- chloro-5-methyl-4-oxo-2,3,4,5- tetrahydrobenzo[b] [1,4]oxazepin-3-yl)- 1H-pyrazole-3-carboxamide

¹H NMR (DMSO-d₆) 13.21 (s, 1H), 8.10 (d, J = 8.1 Hz, 1H), 7.65 (d, J =2.5 Hz, 1H), 7.06-7.51 (m, 5H), 6.37 (d, J = 1.8 Hz, 2H), 4.84 (dt, J =11.6, 7.9 Hz, 1H), 4.31-4.67 (m, 2H), 3.99 (s, 2H), 3.18- 3.41 (m, 3H)411   A 216 (S)-N-(4-oxo-2,3,4,5- tetrahydrobenzo[b][1,4]oxazepin-3-yl)- 3-phenoxy benzamide

¹H NMR (DMSO-d₆) δ: 10.06 (s, 1H), 8.75 (d, J = 8.3 Hz, 1H), 7.65-7.70(m, 1H), 7.48-7.55 (m, 2H), 7.38- 7.45 (m, 2H), 7.09-7.24 (m, 6H),7.01-7.06 (m, 2H), 4.81-4.93 (m, 1H), 4.50 (dd, J = 11.5, 10.6 Hz, 1H),4.41 (dd, J = 10.6, 7.0 Hz, 1H) 375   A 217 (S)-N-(4-oxo-2,3,4,5-tetrahydrobenzo[b] [1,4]oxazepin-3-yl)- 5-pentyl-1H- pyrazole-3-carboxamide

¹H NMR (DMSO-d₆) δ: 13.01 (br s, 1H), 10.13 (s, 1H), 8.06 (d, J = 7.8Hz, 1H), 7.10-7.18 (m, 4H), 6.39 (d, J = 1.8 Hz, 1H), 4.76-4.83 (m, 1H),4.39-4.49 (m, 2H), 2.60 (t, J = 7.6 Hz, 2H), 1.59 (quin, J = 7.5 Hz,2H), 1.19- 1.36 (m, 4H), 0.86 (t, J = 6.9 Hz, 3H) 343   A 218(S)-N-(4-oxo-2,3,4,5- tetrahydrobenzo[b] [1,4]oxazepin-3-yl)-3-(phenylamino) benzamide

¹H NMR (400 MHz, DMSO- d₆) δ 10.06 (s, 1H), 8.57 (d, J = 8.34 Hz, 1H),8.35 (s, 1H), 7.54 (s, 1H), 7.33 (d, J = 5.05 Hz, 2H), 7.20-7.29 (m,3H), 7.11-7.19 (m, 4H), 7.09 (d, J = 7.58 Hz, 2H), 6.86 (t, J = 7.20 Hz,1H), 4.84-4.93 (m, 1H), 4.47-4.57 (m, 1H), 4.38-4.46 (m, 1H) 374   A 219(S)-N-(5-methyl-4- oxo-2,3,4,5- tetrahydrobenzo[b] [1,4]oxazepin-3-yl)-5-phenoxyfuran-2- carboxamide

¹H NMR (400 MHz, DMSO- d₆) δ 8.44 (d, 1H), 7.51 (dd, J = 1.77, 7.83 Hz,1H), 7.46 (t, J = 8.08 Hz, 2H), 7.23-7.36 (m, 3H), 7.22 (d, J = 3.54 Hz,1H), 7.15-7.20 (m, 1H), 5.88 (d, J = 3.54 Hz, 1H), 4.84 (dt, J = 8.08,11.62 Hz, 1H), 4.54 (dd, J = 9.85, 11.62 Hz, 1H), 4.36 (dd, J = 7.71,9.98 Hz, 1H), 3.33 (s, 3H) 379   A 220 (S)-N-(5-methyl-4- oxo-2,3,4,5-tetrahydrobenzo[b] [1,4]oxazepin-3-yl)- 3-(pyridin-2- yloxy)benzamide

¹H NMR (400 MHz, DMSO- d₆) δ 8.73 (d, J = 8.34 Hz, 1H), 8.16 (dd, J =1.26, 4.80 Hz, 1H), 7.85-7.93 (m, 1H), 7.73 (d, J = 8.08 Hz, 1H), 7.63(t, J = 1.89 Hz, 1H), 7.50-7.57 (m, 2H), 7.34 (dd, 2H), 7.26-7.32 (m,1H), 7.21-7.26 (m, 1H), 7.13- 7.18 (m, 1H), 7.10 (d, J = 8.34 Hz, 1H),4.92 (dt, J = 8.12, 11.81 Hz, 1H), 4.56 (dd, J = 9.98, 11.75 Hz, 1H),4.40 (dd, J = 7.71, 9.98 Hz, 1H), 3.31 (s, 3H) 390   A 221(S)-N-(5-methyl-4- oxo-2,3,4,5- tetrahydrobenzo[b] [1,4]oxazepin-3-yl)-3-(morpholino methyl)benzamide

¹H NMR (400 MHz, DMSO- d₆) δ 8.77 (d, J = 8.53 Hz, 1H), 7.96 (br. s.,2H), 7.56- 7.72 (m, 2H), 7.54 (dd, J = 1.76, 7.78 Hz, 1H), 7.22- 7.39(m, 3H), 4.94 (dt, J = 8.22, 11.67 Hz, 1H), 4.58 (dd, J = 9.91, 11.67Hz, 1H), 4.43 (dd, J = 7.91, 9.91 Hz, 1H), 4.36 (br. s., 1H), 3.79- 4.04(m, 2H), 3.59-3.77 (m, 3H), 3.32 (br. s, 5H) 396   A 222(S)-N-(5-methyl-4- oxo-2,3,4,5- tetrahydrobenzo[b] [1,4]oxazepin-3-yl)-3-(3-(trifluoromethyl) phenoxy)benzamide

¹H NMR (400 MHz, DMSO- d₆) δ 8.78 (d, J = 8.28 Hz, 1H), 7.73 (d, J =8.03 Hz, 1H), 7.61-7.69 (m, 1H), 7.56-7.60 (m, 1H), 7.55 (d, J = 5.52Hz, 1H), 7.53 (d, J = 1.51 Hz, 1H), 7.51 (d, J = 1.76 Hz, 1H), 7.37 (s,1H), 7.26-7.36 (m, 2H), 7.21- 7.26 (m, 1H), 4.91 (dt, J = 8.16, 11.80Hz, 1H), 4.56 (dd, J = 10.04, 11.80 Hz, 1H), 4.40 (dd, J = 7.78, 9.79Hz, 1H), 3.31 (s, 3H) 457   A 223 (S)-3- (cyclopentyloxy)-N-(5-methyl-4-oxo- 2,3,4,5- tetrahydrobenzo[b] [1,4]oxazepin-3-yl)benzamide

¹H NMR (400 MHz, DMSO- d₆) δ 8.64 (d, J = 8.53 Hz, 1H), 7.52 (dd, J =1.76, 7.78 Hz, 1H), 7.33-7.43 (m, 3H), 7.32 (t, J = 2.51 Hz, 1H),7.26-7.31 (m, 1H), 7.21- 7.26 (m, 1H), 7.10 (dt, J = 1.98, 7.59 Hz, 1H),4.90- 4.98 (m, 1H), 4.84-4.90 (m, 1H), 4.58 (dd, J = 9.91, 11.67 Hz,1H), 4.40 (dd, J = 7.78, 9.79 Hz, 1H), 3.31 (s, 3H), 1.84-1.99 (m, 1H),1.65- 1.77 (m, 3H), 1.53-1.65 (m, 2H) 381   A 224 (S)-N-(5-methyl-4-oxo-2,3,4,5- tetrahydrobenzo[b] [1,4]oxazepin-3-yl)- 2-phenoxyisonicotinamide

¹H NMR (400 MHz, DMSO- d₆) δ 9.03 (d, J = 8.34 Hz, 1H), 8.30 (d, J =5.05 Hz, 1H), 7.47-7.55 (m, 2H), 7.41-7.47 (m, 2H), 7.39 (s, 1H),7.27-7.37 (m, 2H), 7.21-7.27 (m, 2H), 7.13- 7.19 (m, 2H), 4.91 (dt, J =7.99, 11.81 Hz, 1H), 4.56 (dd, J = 10.11, 11.62 Hz, 1H), 4.44 (dd, J =7.83, 9.85 Hz, 1H), 3.32 (s, 3H) 390   A 225 (S)-5-(4- bromophenoxy)-N-(5-methyl-4-oxo- 2,3,4,5- tetrahydrobenzo[b] [1,4]oxazepin-3-yl)furan-2- carboxamide

¹H NMR (400 MHz, DMSO- d₆) δ 8.47 (d, J = 8.28 Hz, 1H), 7.60-7.66 (m,1H), 7.52 (dd, J = 1.76, 7.78 Hz, 1H), 7.26-7.35 (m, 2H), 7.23 (q, J =2.76 Hz, 1H), 7.13-7.19 (m, 1H), 5.96 (d, J = 3.76 Hz, 1H), 4.84 (dt, J= 8.16, 11.80 Hz, 1H), 4.54 (dd, J = 10.04, 11.54 Hz, 1H), 4.36 (dd, J =7.78, 9.79 Hz, 1H), 3.31 (s, 3H), 2.08 (s, 1H) 459   A 226(S)-5-((4-methyl-1H- pyrazol-1-yl)methyl)- N-(5-methyl-4-oxo- 2,3,4,5-tetrahydrobenzo[b] [1,4]oxazepin-3- yl)furan-2- carboxamide

¹H NMR (400 MHz, DMSO- d₆) δ 8.48 (d, 1H), 7.54 (s, 1H), 7.52 (dd, J =1.89, 7.71 Hz, 1H), 7.28-7.36 (m, 2H), 7.21-7.28 (m, 2H), 7.15 (d, J =3.54 Hz, 1H), 6.51 (d, J = 3.54 Hz, 1H), 5.33 (s, 2H), 4.84 (dt, J =8.27, 11.75 Hz, 1H), 4.54 (dd, J = 9.85, 11.62 Hz, 1H), 4.37 (dd, J =7.71, 9.73 Hz, 1H), 3.31 (s, 2H), 2.00 (s, 2H) 381   A 227 (S)-5-((3,5-dimethylisoxazol-4- yl)methyl)-N-(5- methyl-4-oxo- 2,3,4,5-tetrahydrobenzo[b] [1,4]oxazepin-3- yl)thiophene-2- carboxamide

¹H NMR (400 MHz, DMSO- d₆) δ 8.59 (d, J = 8.28 Hz, 1H), 8.21 (s, 1H),7.52 (dd, J = 1.76, 7.78 Hz, 1H), 7.20- 7.42 (m, 7H), 5.74 (s, 2H), 4.87(dt, J = 8.03, 11.54 Hz, 1H), 4.59 (dd, J = 10.04, 11.54 Hz, 1H), 4.40(dd, J = 7.91, 9.91 Hz, 1H), 3.31 (s, 3H), 1.21 (d, J = 6.27 Hz, 1H)412   A 228 (S)-2-benzyl-N-(5- methyl-4-oxo- 2,3,4,5- tetrahydrobenzo[b][1,4]oxazepin-3- yl)thiazole-4- carboxamide

¹H NMR (400 MHz, DMSO- d₆) δ 8.41 (d, J = 7.78 Hz, 1H), 8.16 (s, 1H),7.51 (dd, J = 1.88, 7.65 Hz, 1H), 7.38 (d, J = 4.52 Hz, 3H), 7.29-7.37(m, 4H), 7.27 (td, J = 1.88, 7.84 Hz, 1H), 4.86 (dt, J = 7.87, 11.36 Hz,1H), 4.54- 4.64 (m, 1H), 4.45 (dd, J = 7.78, 9.79 Hz, 1H), 4.42 (s, 2H),2.08 (s, 1H) 394   A 229 (S)-2-(4- bromobenzyl)-N-(5- methyl-4-oxo-2,3,4,5- tetrahydrobenzo[b] [1,4]oxazepin-3- yl)thiazole-4- carboxamide

¹H NMR (400 MHz, DMSO- d₆) δ 8.10 (d, 1H), 7.51 (dd, J = 1.76, 7.78 Hz,1H), 7.20- 7.36 (m, 3H), 6.41 (s, 1H), 4.84 (dt, J = 7.91, 11.54 Hz,1H), 4.47-4.56 (m, 1H), 4.41 (dd, J = 7.91, 9.91 Hz, 1H), 2.60 (t, J =7.65 Hz, 2H), 1.57 (dt, J = 7.59, 14.93 Hz, 2H), 1.29 (dq, J = 7.34,14.87 Hz, 2H), 0.89 (t, J = 7.40 Hz, 3H) 472   474   A 230(S)-N-(5-methyl-4- oxo-2,3,4,5- tetrahydrobenzo[b] [1,4]oxazepin-3-yl)-3-(p-tolyloxy) benzamide

¹H NMR (400 MHz, DMSO- d₆) δ 8.72 (d, J = 8.53 Hz, 1H), 7.62 (d, J =8.03 Hz, 1H), 7.44-7.53 (m, 2H), 7.41-7.45 (m, 1H), 7.26-7.36 (m, 2H),7.20-7.25 (m, 3H), 7.17 (dd, J = 1.63, 8.16 Hz, 1H), 6.95 (d, J = 8.53Hz, 2H), 4.90 (dt, J = 8.06, 11.73 Hz, 1H), 4.56 (dd, J = 10.04, 11.80Hz, 1H), 4.39 (dd, J = 7.91, 9.91 Hz, 1H), 3.31 (s, 3H), 2.30 (s, 3H)403   A 231 ((S)-5- (cyclohexylmethyl)- N-(5-methyl-7-(5- methyl-1,3,4-oxadiazol-2-yl)-4- oxo-2,3,4,5- tetrahydrobenzo[b] [1,4]oxazepin-3-yl)-4H-1,2,4-triazole-3- carboxamide

¹H NMR (DMSO-d₆) δ: 14.17 (s, 1H), 8.42 (d, J = 7.8 Hz, 1H), 8.04 (d, J= 2.0 Hz, 1H), 7.89 (dd, J = 8.3, 2.0 Hz, 1H), 7.45 (d, J = 8.3 Hz, 1H),4.91 (dt, J = 11.6, 7.7 Hz, 1H), 4.65-4.73 (m, 1H), 4.50 (dd, J = 9.9,7.3 Hz, 1H), 3.39 (s, 3H), 2.61-2.68 (m, 2H), 2.61 (s, 3H), 0.90- 1.76(m, 11H) 466.3 F 232 (S)-5-benzyl-N-(2- oxo-2,3,4,5- tetrahydro-1H-benzo[b][1,4] diazepin-3- yl)isoxazole-3- carboxamide

¹H NMR (DMSO-d₆, 400 MHz): δ = 8.72 (d, J = 7.8 Hz, 1 H), 7.21-7.48 (m,6 H), 7.07-7.17 (m, 1 H), 6.96- 7.06 (m, 2 H), 6.55 (s, 1 H), 5.30 (d, J= 4.5 Hz, 1 H), 4.59 (dt, J = 11.7, 7.2 Hz, 1 H), 4.22 (s, 2 H),3.47-3.69 (m, 2 H), 3.14 (t, J = 7.2 Hz, 1 H). 363   F 233(S)-5-benzyl-N-(1- methyl-4-oxo- 2,3,4,5-tetrahydro- 1H-benzo[b][1,4]diazepin-3- yl)isoxazole-3- carboxamide

¹H NMR (DMSO-d₆, 400 MHz): δ = 9.90 (s, 1 H), 8.71 (d, J = 7.8 Hz, 1 H),6.92- 7.45 (m, 9 H), 6.56 (s, 1 H), 4.51 (dt, J = 12.1, 7.3 Hz, 1 H),4.22 (s, 2 H), 3.65 (dd, J = 11.9, 10.1 Hz, 1 H), 3.17- 3.31 (m, 1 H),2.74 ppm (s, 3 H) 377   F 234 (S)-N-(1,5-dimethyl- 2-oxo-2,3,4,5-tetrahydro-1H- benzo[b][1,4] diazepin-3-yl)-5-(4- methylbenzyl)-1H-pyrazole-3- carboxamide

¹H NMR (DMSO-d₆, 400 MHz): δ = 13.17 (br. s., 1 H), 7.93 (d, J = 7.6 Hz,1 H), 6.89-7.56 (m, 8 H), 6.33 (s, 1 H), 4.35-4.67 (m, 1 H), 3.92 (s, 2H), 3.49 (t, 1 H), 3.34 (s, 3 H), 2.71 (s, 3 H), 2.69 (s, 1 H), 2.26 ppm(s, 3 H) 404   F 235 (S)-5-benzyl-N-(1- methyl-2-oxo-2,3,4,5-tetrahydro- 1H-benzo[b] [1,4]diazepin-3- yl)isoxazole-3-carboxamide

¹H NMR (DMSO-d₆, 400 MHz): δ = 8.66 (d, J = 7.8 Hz, 1 H), 7.22-7.44 (m,6 H), 7.07-7.17 (m, 1 H), 6.96- 7.06 (m, 2 H), 6.55 (s, 1 H), 5.32 (d, J= 4.5 Hz, 1 H), 4.65 (dt, J = 11.7, 7.0 Hz, 1 H), 4.22 (s, 2 H),3.47-3.69 (m, 2 H), 3.33 ppm (s, 3 H) 377   F 236 (S)-5-benzyl-N-(2-oxo-2,3,4,5- tetrahydro-1H- benzo[b]azepin-3- yl)isoxazole-3-carboxamide

1H NMR (DMSO-d6) δ: 9.93 (s, 1H), 8.65 (d, J = 7.6 Hz, 1H), 7.23-7.40(m, 7H), 7.11-7.19 (m, 1H), 7.04 (d, J = 7.6 Hz, 1H), 6.54 (s, 1H),4.27-4.48 (m, 1H), 4.21 (s, 2H), 2.63-2.83 (m, 2H), 2.17-2.39 (m, 2H)362.0 F 237 (S)-N-(6-fluoro-8- methyl-4-oxo- 2,3,4,5- tetrahydrobenzo[b][1,4]oxazepin-3-yl)- 5-((5-methyl thiophen-2- yl)methyl)-4H-1,2,4-triazole-3- carboxamide

1H NMR (DMSO-d6) δ: 14.53 (br. s., 1H), 10.02 (s, 1H), 8.49 (br. s.,1H), 6.97- 7.03 (m, 1H), 6.90 (s, 1H), 6.73 (d, J = 3.3 Hz, 1H), 6.61-6.65 (m, 1H), 4.85 (dt, J = 11.4, 7.6 Hz, 1H), 4.63 (t, J = 10.7 Hz,1H), 4.46 (dd, J = 10.1, 7.3 Hz, 1H), 4.23 (s, 2H), 2.38 (s, 3H), 2.30(s, 3H) 416.2 F 238 (S)-5-benzyl-N-(8- methoxy-1-methyl-2- oxo-2,3,4,5-tetrahydro-1H- benzo[b]azepin-3-yl)- 4H-1,2,4-triazole-3- carboxamide

¹H NMR (400 MHz, DMSO- d₆) δ ppm 14.35 (br. S., 1 H), 8.19 (br. s., 1 H)7.23-7.33 (m, 6 H) 6.99 (d, J = 8.5 Hz, 1 H), 6.85 (dd, J = 8.28, 2.26Hz, 1 H) 4.31-4.44 (m, 1 H) 4.12 (br. s., 2 H) 3.79 (s, 3 H) 3.31 (s, 3H) 2.56-2.68 (m, 2 H) 2.25-2.40 (m, 1 H) 2.14 (s, 1 H) 406.2 H 239(S)-5-(3- fluorobenzyl)-N-(8- methoxy-1-methyl-2- oxo-2,3,4,5-tetrahydro-1H- benzo[b]azepin-3-yl)- 4H-1,2,4-triazole-3- carboxamide

¹H NMR (400 MHz, DMSO- d₆) δ ppm 14.31 (br. S., 1 H), 8.21 (br. s., 1 H)7.37 (q, J = 7.4 Hz, 1 H) 7.25 (d, J = 8.5 Hz, 1 H) 7.03-7.19 (m, 3 H)6.93-7.03 (m, 1 H) 6.84 (dd, J = 8.28, 2.26 Hz, 1 H) 4.27- 4.43 (m, 1 H)4.15 (br. s., 2 H) 3.79 (s, 3 H) 3.31 (s, 3 H) 2.59-2.71 (m, 2 H) 2.32(d, J = 8.03 Hz, 1 H) 2.08 (s, 1 H) 424.2 H 240 (S)-5-benzyl-N-(6,8-difluoro-4-oxo- 2,3,4,5- tetrahydrobenzo[b] [1,4]oxazepin-3-yl)-4H-1,2,4-triazole-3- carboxamide

1H NMR (DMSO-d6) δ: 14.45 (br. s., 1H), 10.09 (s, 1H), 8.46 (br. s.,1H), 7.20- 7.37 (m, 6H), 7.04 (dt, J = 9.3, 2.3 Hz, 1H), 4.90 (dt, J =11.2, 7.5 Hz, 1H), 4.67 (t, J = 10.7 Hz, 1H), 4.51 (dd, J = 10.1, 7.1Hz, 1H), 4.13 (s, 2H). 400.2 H 241 (S)-5-isopentyl-N-(5-methyl-7-(5-methyl- 1,3,4-oxadiazol-2- yl)-4-oxo-2,3,4,5-tetrahydrobenzo[b] [1,4]oxazepin-3-yl)- 4H-1,2,4-triazole-3- carboxamide

¹H NMR (DMSO-d₆) δ: 14.16 (br. s., 1H), 8.33-8.45 (m, 1H), 8.04 (d, J =1.8 Hz, 1H), 7.89 (dd, J = 8.5, 1.9 Hz, 1H), 7.45 (d, J = 8.3 Hz, 1H),4.91 (dt, J = 11.5, 7.8 Hz, 1H), 4.69 (t, J = 11.7 Hz, 1H), 4.51 (dd, J= 9.6, 7.6 Hz, 1H), 3.39 (s, 3H), 2.73 (d, J = 7.6 Hz, 2H), 2.61 (s,3H), 1.50-1.63 (m, 3H), 0.91 (d, J = 6.3 Hz, 6H); MS (m/z): 440.2 H 242(S)-5-benzyl-N-(5- methyl-8-(5-methyl- 1,3,4-oxadiazol-2-yl)-4-oxo-2,3,4,5- tetrahydrobenzo[b] [1,4]oxazepin-3-yl)-4H-1,2,4-triazole-3- carboxamide

1H NMR (DMSO-d6) δ: 14.41 (br. s., 1H), 8.53 (br. s., 1H), 7.91 (dd, J =8.3, 2.0 Hz, 1H), 7.78 (d, J = 2.0 Hz, 1H), 7.71 (d, J = 8.3 Hz, 1H),7.22-7.36 (m, 5H), 4.89 (dt, J = 11.6, 7.9 Hz, 1H), 4.71 (t, J = 10.7Hz, 1H), 4.52 (dd, J = 9.7, 7.7 Hz, 1H), 4.13 (s, 2H), 3.36 (s, 3H),2.60 (s, 3H); 460.2 F

The following compounds were prepared via the oxidation methodindicated.

243 5-benzyl-N-((3R)-1- oxido-4-oxo-2,3,4,5- tetrahydrobenzo[b][1,4]thiazepin-3- yl)isoxazole-3- carboxamide

1H NMR (400 MHz, DMSO-d6) δ = 10.34 (br. s., 1 H), 9.24-8.70 (m, 1 H),7.87-7.52 (m, 2 H), 7.48-7.12(m, 6 H), 6.53 (s, 1 H), 4.88-4.55 (m, 1H), 4.22 (s, 3 H), 4.03 (dd, J = 7.6, 14.4 Hz, 1H), 3.56 (dd, J = 11.0,14.5 Hz, 1H) 396 C 244 (R)-5-benzyl-N-(1,1- dioxido-4-oxo- 2,3,4,5-tetrahydrobenzo[b] [1,4]thiazepin-3- yl)isoxazole-3- carboxamide

1H NMR (MeOH-d4) 8.06 (dd, J = 7.8, 1.3 Hz, 1H), 7.81 (d, J = 1.5 Hz,1H), 7.48-7.68 (m, 1H), 7.15- 7.45 (m, 8H), 6.41 (s, 1H), 4.97 (dd, J =11.6, 7.3 Hz, 1H), 4.10-4.31 (m, 2H), 3.89-4.07 (m, 2H) 412 B

The following compounds were prepared via acylation or isocyanateaddition of the appropriate amine using the method indicated.

245 (S)-methyl (3-(5- benzylisoxazole-3- carboxamido)-5- methyl-4-oxo-2,3,4,5- tetrahydrobenzo[b] [1,4]oxazepin-7- yl)carbamate

¹H NMR (DMSO-d₆) δ: 9.80 (s, 1H), 8.85 (d, J = 8.1 Hz, 1H), 7.55 (d, J =2.3 Hz, 1H), 7.25-7.38 (m, 6H), 7.15 (d,J = 8.8 Hz, 1H), 6.55 (s, 1H),4.83 (dt, J = 11.5, 8.0 Hz, 1H), 4.49-4.56 (m, 1H), 4.35 (dd, J = 9.9,7.8 Hz, 1H), 4.22 (s, 2H), 3.68 (s, 3H), 3.26 (s, 3H). 451.2 J 246(S)-5-benzyl-N-(5- methyl-7-(1-methyl- 1H-pyrazole-4-carboxamido)-4-oxo- 2,3,4,5- tetrahydrobenzo[b] [1,4]oxazepin-3-yl)isoxazole-3- carboxamide

¹H NMR (DMSO-d₆) δ: 9.96 (s, 1H), 8.86 (d, J = 8.3 Hz, 1H), 8.31 (s,1H), 8.02 (s, 1H), 7.83 (d, J = 2.3 Hz, 1H), 7.58 (dd, J = 8.8, 2.5 Hz,1H), 7.26- 7.38 (m, 5H), 7.19 (d, J = 8.8 Hz, 1H), 6.55 (s, 1H), 4.87(dt, J = 11.6, 8.0 Hz, 1H), 4.51-4.58 (m, 1H), 4.38 (dd, J = 9.9, 7.8Hz, 1H), 4.22 (s, 2H), 3.91 (s, 3H), 3.30 (s, 3H). 501.4 J 247(S)-5-benzyl-N-(5- methyl-7-(N- methylacetamido)-4- oxo-2,3,4,5-tetrahydrobenzo[b] [1,4]oxazepin-3- yl)isoxazole-3- carboxamide

¹H NMR (DMSO-d₆) δ: 8.87 (d, 1H), 7.56-7.61 (m, 1H), 7.24-7.38 (m, 7H),6.54 (s, 1H), 4.88 (dt, J = 11.5, 8.0 Hz, 1H), 4.60 (t, J = 10.7 Hz,1H), 4.41- 4.47 (m, 1H), 4.22 (s, 2H), 3.31 (s, 3H), 3.18 (br. s., 3H),1.83 (br. s., 3H) 449.2 J 248 (S)-5-benzyl-N-(7- (3-methoxypropanamido)-5- methyl-4-oxo- 2,3,4,5- tetrahydrobenzo[b][1,4]oxazepin-3- yl)isoxazole-3- carboxamide

¹H NMR (DMSO-d₆) δ: 10.12 (s, 1H), 8.85 (d, J = 8.1 Hz, 1H), 7.75 (d, J= 2.5 Hz, 1H), 7.26-7.43 (m, 6H), 7.16 (d, J = 8.6 Hz, 1H), 6.55 (s,1H), 4.84 (dt, J = 11.6, 8.1 Hz, 1H), 4.49-4.57 (m, 1H), 4.33- 4.39 (m,1H), 4.22 (s, 2H), 3.62 (t, J = 6.2 Hz, 2H), 3.27 (s, 3H), 3.25 (s, 3H),2.55 (t, 2H). 479.2 J 249 (S)-5-benzyl-N-(7-(3- ethylureido)-5-methyl-4-oxo- 2,3,4,5- tetrahydrobenzo[b] [1,4]oxazepin-3-yl)isoxazole-3- carboxainide

¹H NMR (DMSO-d₆) δ: 8.85 (d, J = 8.1 Hz, 1H), 8.58 (s, 1H), 7.57 (d, J =2.5 Hz, 1H), 7.26-7.38 (m, 5H), 7.15-7.20 (m, 1H), 7.04-7.09 (m, 1H),6.55 (s, 1H), 6.17 (t, J = 5.6 Hz, 1H), 4.79-4.87 (m, 1H), 4.46-4.53 (m,1H), 4.33 (dd, J = 9.9, 7.8 Hz, 1H), 4.22 (s, 2H), 3.26 (s, 3H),3.07-3.15 (m, 2H), 1.05 (t, 3H). 464.3 G 250 (S)-5-benzyl-N-(7-(3-(2-methoxyethyl) ureido)-5-methyl-4- oxo-2,3,4,5- tetrahydrobenzo[b][1,4]oxazepin-3- yl)isoxazole-3- carboxamide

¹H NMR (DMSO-d₆) δ: 8.83 (d, J = 8.3 Hz, 1H), 8.69 (s, 1H), 7.56 (d, J =2.3 Hz, 1H), 7.25-7.39 (m, 5H), 7.14-7.17 (m, 1H), 7.06-7.10 (m, 1H),6.55 (s, 1H), 6.26 (t, J = 5.6 Hz, 1H), 4.84 (dt, J = 11.4, 8.1 Hz, 1H),4.46- 4.53 (m, 1H), 4.33 (dd, J = 9.9, 7.8 Hz, 1H), 4.22 (s, 2H),3.37-3.40 (m, 2H), 3.24-3.29 (m, 8H). 494.4 G

The following compounds were prepared via Suzuki coupling using themethod indicated.

251 (S)-5-benzyl-N-(7- (1-methyl-1H- pyrazol-3-yl)-2-oxo-2,3,4,5-tetrahydro- 1H-benzo[b]azepin- 3-yl)-4H-1,2,4- triazole-3-carboxamide

1H NMR (400 MHz, DMSO-d6) δ ppm 2.12- 2.42 (m, 2 H) 2.78 (m, 2 H) 3.88(s, 3 H) 4.11 (br. s., 2 H) 4.37 (dt, J = 11.43, 7.93 Hz, 1 H) 6.68 (d,J = 2.27 Hz, 1 H) 7.05 (d, J = 8.08 Hz, 1 H) 7.18- 7.39 (m, 5 H) 7.68(dd, J = 8.21, 1.89 Hz, 1 H) 7.74 (dd, J = 8.84, 2.02 Hz, 2 H) 8.22 (br.s., 1 H) 10.03 (s, 1H) 442 I

The following compounds were prepared via coupling of the appropriateamine and acid using the method indicated.

252 (S)-5-benzyl-N-(2,5- dimethyl-6-oxo- 6,7,8,9-tetrahydro-5H-pyrimido[4,5- b][1,4]diazepin-7- yl)-4H-1,2,4-triazole- 3-carboxamide

¹H NMR (DMSO-d₆) δ: 14.45 (br. s., 1H), 8.37 (br. s., 1H), 8.24 (s, 1H),7.84 (d, J = 7.3 Hz, 1H), 7.15- 7.40 (m, 5H), 4.68 (t, J = 7.5 Hz, 1H),4.13 (br. s., 2H), 3.57-3.67 (m, 1H), 3.41-3.50 (m, 1H), 3.31 (s, 3H),2.38 (s, 3H) 393 F 253 (S)-5-benzyl-N-(8- fluoro-1-methyl-2-oxo-2,3,4,5- tetrahydro-1H- pyrido[2,3-b] [1,4]diazepin-3-yl)-4H-1,2,4-triazole-3- carboxamide

¹H NMR (DMSO-d₆) δ: 14.40 (br. s., 1H), 8.37 (br. s., 1H), 8.02 (d, J =2.5 Hz, 1H), 7.74 (dd, J = 9.6, 2.8 Hz, 1H), 7.22-7.38 (m, 5H), 6.44 (d,J = 6.6 Hz, 1H), 4.72 (ddd, J = 11.5, 6.9, 4.5 Hz, 1H), 4.12 (s, 2H),3.74 (ddd, J = 11.0, 6.7, 4.5 Hz, 1H), 3.44- 3.55 (m, 1H), 3.29 (s, 3H)396 F 254 (S)-5-benzyl-N-(7- bromo-5-methyl-4- oxo-2,3,4,5-tetrahydrobenzo [b][1,4]oxazepin-3- yl)-4H-1,2,4-triazole- 3-carboxamide

¹H NMR (DMSO-d₆) δ: 8.38-8.66 (m, 1H), 7.77 (d, J = 2.5 Hz, 1H), 7.02-7.60 (m, 7H), 4.85 (dt, J = 11.6, 7.8 Hz, 1H), 4.62 (t, J = 10.7 Hz,1H), 4.41 (dd, J = 9.9, 7.6 Hz, 1H), 4.12 (s, 2H), 3.18-3.43 (m, 456/458H 255 5-benzyl-N-(7-(1H- pyrazol-4-yl)-5- methyl-4-oxo- 2,3,4,5-tetrahydrobenzo [b][1,4]oxazepin-3- yl)-4H-1,2,4-triazole- 3-carboxamide

¹H NMR (CDCl₃) δ: 8.10 (d, J = 7.3 Hz, 1H), 7.85 (s, 2H), 7.12-7.47 (m,8H), 5.12 (br. s., 1H), 4.63- 4.82 (m, 1H), 4.32 (t, J = 10.5 Hz, 1H),4.21 (s, 2H), 3.48 (s, 3H) 444 I 256 ((S)-N-(6-fluoro-8- methyl-4-oxo-2,3,4,5- tetraliydrobenzo[b] [1,4]oxazepin-3-yl)- 5-(2-fluorobenzyl)-4H-1,2,4-triazole-3- carboxamide

¹H NMR (DMSO-d₆) δ: 14.49 (none, 1H), 10.00 (s, 1H), 8.28-8.68 (m, 1H),6.73-7.53 (m, 6H), 4.84 (dt, J = 11.1, 7.6 Hz, 1H), 4.61 (t, J = 10.6Hz, 1H), 4.45 (dd, J = 10.1, 7.3 Hz, 1H), 4.15 (s, 2H), 2.30 (s, 3H) 414H 257 (S)-5-benzyl-N-(8- (difluoromethoxy)-5- methyl-4-oxo- 2,3,4,5-tetrahydrobenzo[b] [1,4]oxazepin-3-yl)- 4H-1,2,4-triazole-3- carboxamide

¹H NMR (DMSO-d₆) δ: 14.37 (br. s., 1H), 8.42 (d, J = 8.1 Hz, 1H), 7.57(d, J = 8.8 Hz, 1H), 7.09-7.38 (m, 8H), 4.85 (dt, J = 11.6, 7.8 Hz, 1H),4.62 (t, J = 10.9 Hz, 1H), 4.44 (dd, J = 9.9, 7.6 Hz, 1H), 4.15 (s, 2H),3.30 (s, 3H) 444 F 258 (S)-N-(5-methyl-7- (5-methyl-l,3,4-oxadiazol-2-yl)-4- oxo-2,3,4,5- tetrahydrobenzo[b] [1,4]oxazepin-3-yl)-5-(thiophen-2- ylmethyl)-4H-1,2,4- triazole-3- carboxamide

NA 466 F 259 (S)-1-benzyl-N-(5- methyl-7-(5-methyl- 1,3,4-oxadiazol-2-yl)-4-oxo-2,3,4,5- tetrahydrobenzo[b] [1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3- carboxamide

Very broad signals observed in ¹H NMR run in DMSO-d₆. 460 F 260(S)-5-benzyl-N-(8- cyclopropyl-5- methyl-4-oxo- 2,3,4,5- tetrahydrobenzo[b][1,4]oxazepin-3- yl)-4H-1,2,4-triazole- 3-carboxamide

¹H NMR (DMSO-d₆) δ:14.34 (br. s., 1H), 8.33 (d, J = 7.6 Hz, 1H), 7.22-7.61 (m, 7H), 6.84-7.03 (m, 1H), 4.08-5.08 (m, 3H), 4.01 (s, 2H), 3.27(s, 3H), 0.58-1.46 (m, 5H) 418 H 261 (S)-N-(7-cyano-5,8- dimethyl-4-oxo-2,3,4,5- tetrahydrobenzo[b] [1,4]oxazepin-3-yl)- 5-(4-methylbenzyl)-4H-1,2,4-triazole-3- carboxamide

¹H NMR (DMSO-d₆) δ: 14.31 (br. s., 1H), 8.39 (d, J = 7.1 Hz, 1H), 8.02(s, 1H), 7.34 (s, 1H), 7.14 (m, 4H), 4.86 (m, 1H), 4.68 (m, 1H), 4.45(m, 1H), 4.09 (s, 2H), 3.33 (s, 3H), 3.31 (s, 3H), 2.27 (s, 3H) 431 H262 (S)-N-(6-fluoro-8- methyl-4-oxo- 2,3,4,5- tetrahydrobenzo[b][1,4]oxazepin-3-yl)- 5-(thiophen-2- ylmethyl)-4H-1,2,4- triazole-3-carboxamide

1H NMR (DMSO-d6) δ: 14.56 (br. s., 1H), 10.02 (s, 1H), 8.53 (br. s.,1H), 7.37- 7.43 (m, 1H), 6.87-7.03 (m, 3H), 6.48-6.59 (m, 1H), 4.85 (dt,J = 11.4, 7.6 Hz, 1H), 4.63 (t, J = 10.7 Hz, 1H), 4.46 (dd, J = 10.1,7.3 Hz, 1H), 4.33 (s, 2H), 2.30 (s, 3H) 402 F 263 (S)-5-benzyl-N-(6-chloro-4-oxo-2,3,4,5- tetrahydrobenzo [b][1,4]oxazepin-3-yl)-4H-1,2,4-triazole- 3-carboxamide

¹H NMR (DMSO-d₆) δ: 10.01 (br. s., 1H), 8.51 (br. s., 1H), 7.17-7.48 (m,9H), 4.81 (dt, J = 11.3, 7.9 Hz, 1H), 4.66 (t, J = 10.7 Hz, 1H), 4.47(dd, J = 9.9, 7.8 Hz, 1H), 4.12 (s, 2H) 399 H 264 (S)-N-(5-methyl-4-oxo-2,3,4,5- tetrahydrobenzo [b][1,4]oxazepin-3- yl)-5-phenethyl-4H-1,2,4-triazole-3- carboxamide

1H NMR (DMSO-d6) δ: 14.18 (br. s., 1H), 8.37 (br. s., 1H), 7.52 (d, J =7.5 Hz, 1H), 7.11-7.40 (m, 8H), 4.79-4.90 (m, 1H), 4.54- 4.63 (m, 1H),4.39-4.48 (m, 1H), 3.33 (s, 3H), 3.05 (br. s., 4H⁾ 392 F 265(S)-5-benzyl-N-(7- (difluoromethoxy)-5- methyl-4-oxo- 2,3,4,5-tetrahydrobenzo [b][1,4]oxazepin-3- yl)-4H-1,2,4-triazole- 3-carboxamide

¹H NMR (DMSO-d₆) δ: 14.35 (br. s., 1H), 8.43 (br. s., 1H), 7.06-7.49 (m,9H), 4.86 (dt, J = 11.3, 8.0 Hz, IH), 4.55-4.68 (m, 1H), 4.35-4.47 (m,1H), 4.13 (br. s., 2H), 3.32 (s, 3H) 444 F 266 (S)-5-(2-cyclopentylethyl)-N- (6-fluoro-8-methyl-4- oxo-2,3,4,5- tetrahydrobenzo[b][1,4]oxazepin-3- yl)-4H-1,2,4-triazole- 3-carboxamide

¹H NMR (DMSO-d₆) δ: 14.24 (br. s., 1H), 10.01 (br. s., 1H), 8.38 (br.s., 1H), 6.99 (dd, J = 10.7, 1.1 Hz, 1H), 6.90 (s, 1H), 4.85 (dt, J =11.1, 7.6 Hz, 1H), 4.61 (t, J = 10.6 Hz, 1H), 4.46 (dd, J = 10.1, 7.3Hz, 1H), 2.74 (t, J = 7.3 Hz, 2H), 2.31 (s, 3H), 1.66- 1.79 (m, 6H),1.44-1.62 (m, 5H) 402 F 267 (S)-N-(7-chloro-2- oxo-2,3,4,5-tetrahydro-1H- benzo[b]azepin-3-yl)- 5-(cyclopentyl methyl)-4H-1,2,4-triazole-3- carboxamide

¹H NMR (DMSO-d₆) δ: 10.09 (s, 1H), 8.25 (br. s., 1H), 7.45 (d, J = 2.3Hz, 1H), 7.35 (dd, J = 8.3, 2.5 Hz, 1H), 7.05 (d, J = 8.3 Hz, 1H), 4.33(dt, J = 11.6, 7.8 Hz, 1H), 3.09-3.56 (m, 2H), 2.24 (dt, J = 15.1, 7.5Hz, 2H), 1.37-1.86 (m, 5H), 1.01-1.34 (m, 3H) 388 F 268(S)-5-benzyl-N-(5,8- dimethyl-7-(5- methyl-1,3,4- oxadiazol-2-yl)-4-oxo-2,3,4,5- tetrahydrobenzo [b][1,4]oxazepin-3- yl)-4H-1,2,4-triazole-3-carboxamide

¹H NMR (DMSO-d₆) δ: 8.29-8.63 (m, 1H), 7.91 (s, 1H), 7.09-7.52 (m, 7H),4.90 (dt, J = 11.6, 7.7 Hz, 1H), 4.67 (br. s., 1H), 4.46 (dd, J = 9.9,7.3 Hz, 1H), 4.12 (br. s., 2H), 3.32 (s 3H), 2.54-2.68 (m, 6H) 474 F 269N-((S)-6-fluoro-8- methyl-4-oxo- 2,3,4,5- tetrahydrobenzo[b][1,4]oxazepin-3- yl)-5-((tetrahydro- 2H-pyran-3- yl)methyl)-4H-1,2,4-triazole-3- carboxamide

Complex ¹H NMR due to diastereoisomer mixture 404 F 270(S)-5-(cyclopentyl methyl)-N-(5,8- dimethyl-7-(5- methyl-1,3,4-oxadiazol-2-yl)-4- oxo-2,3,4,5- tetrahydrobenzo [b][1,4]oxazepin-3-yl)-4H-1,2,4-triazole- 3-carboxamide

¹H NMR (DMSO-d₆) δ: 8.26-8.44 (m, 1H), 7.91 (s, 1H), 7.34 (s, 1H), 4.90(dt, J = 11.6, 7.6 Hz, 1H), 4.66 (br. s., 1H), 4.48 (dd, J = 9.7, 7.5Hz, 1H), 3.36 (s, 3H), 2.72 (d, J = 7.3 Hz, 2H), 2.58-2.65 (m, 6H),2.19-2.30 (m, 1H), 1.43- 1.80 (m, 8H) 466 A 271 (S)-5-benzyl-N-(9-fluoro-7-methyl-2- oxo-2,3,4,5- tetrahydro-1H- benzo[b][1,4]diazepin-3-yl)-4H- 1,2,4-triazole-3- carboxamide

¹H NMR (DMSO-d₆) δ: 14.38 (br. s., 1H), 9.69 (s, 1H), 8.29 (br. s., 1H),7.20- 7.40 (m, 5H), 6.41-6.55 (m, 2H), 6.12 (br. s., 1H), 4.62 (ddd, J =10.4, 6.5, 4.1 Hz, 1H), 4.13 (s, 2H), 3.65-3.71 (m, 2H), 2.19 (s, 3H)395 F 272 (S)-5- (cyclopentylmethyl)- N-(7,9-difluoro-2- oxo-2,3,4,5-tetrahydro-1H- benzo[b]azepin-3-yl)- 4H-1,2,4-triazole-3- carboxamide

¹H NMR (DMSO-d₆) δ: 14.10 (br. s., 1H), 9.97 (s, 1H), 8.25 (br. s., 1H),7.23- 7.37 (m, 1H), 7.16 (d, J = 8.8 Hz, 1H), 4.36 (dt, J = 11.2, 7.9Hz, 1H), 2.76- 2.85 (m, 2H), 2.72 (d, J = 7.3 Hz, 2H), 2.40-2.49 (m,1H), 2.20-2.34 (m, 12H), 1.49-1.75 (m, 6H), 1.15-1.27 (m, 2H) 390 F 273(S)-5-(cyclopentyl methyl)-N-(9-fluoro- 7-methyl-2-oxo-2,3,4,5-tetrahydro- 1H-benzo[b][1,4] diazepin-3-yl)-4H-1,2,4-triazole-3- carboxamide

¹H NMR (DMSO-d₆) δ: 13.94 (br. s., 1H), 9.71 (s, 1H), 8.26 (d J = 5.8Hz, 1H), 6.51 (s, 1H), 6.46 (d, J = 10.8 Hz, 1H), 6.15 (br. s., 1H),4.64 (ddd, J = 10.5, 6.5, 4.0 Hz, 1H), 3.71 (dd, J = 11.0, 3.8 Hz, 1H),3.42- 3.50 (m, 1H), 2.75 (d, J = 7.5 Hz, 2H), 2.23-2.36 (m, 1H), 2.21(s, 3H), 1.48- 1.77 (m,6H), 1.16-1.30 (m, 2H) 387 F 274 (S)-5-(2,6-difluorobenzyl)-N-(6- fluoro-8-methyl-4- oxo-2,3,4,5- tetrahydrobenzo[b][1,4]oxazepin-3- yl)-4H-1,2,4-triazole- 3-carboxamide

¹H NMR (DMSO-d₆) δ: 14.46 (br. s., 1H), 10.01 (s, 1H), 8.39 (br. s.,1H),7.41 (quin, J = 7.5 Hz, 1H), 7.07- 7.18 (m, 2H), 6.99 (d, J = 10.5Hz, 1H), 6.89 (s, 1H), 4.84 (dt, J = 11.2, 7.6 Hz, 1H), 4.57-4.68 (m,1H), 4.44 (dd, J = 10.0, 7.3 Hz, 1H), 4.15 (br. s., 2H), 2.30 (s, 3H)432 F 275 (S)-5-benzyl-N-(5- methyl-7-(5- methyl-1,2,4-oxadiazol-3-yl)-4- oxo-2,3,4,5- tetrahydrobenzo [b][1,4]oxazepin-3-yl)-4H-1,2,4- triazole-3- carboxamide

¹H NMR (DMSO-d₆) δ: 14.45 (br. s., 1H), 8.50 (br. s., 1H), 8.02 (d, J =2.0 Hz, 1H), 7.90 (dd, J = 8.3, 2.0 Hz, 1H), 7.42 (d, J = 8.3 Hz, 1H),7.30-7.36 (m, 2H), 7.22-7.29 (m, 3H), 4.90 (dt, J = 11.6, 7.7 Hz, 1H),4.68 (t, J = 10.7 Hz, 1H), 4.49 (dd, J = 10.0, 7.5 Hz, 1H), 4.12 (s,2H), 3.38 (s, 3H), 2.69 (s, 3H) 460 F 276 (S)-5-(2,3-difluorobenzyl)-N-(6- fluoro-8-methyl-4- oxo-2,3,4,5- tetrahydrobenzo[b][1,4]oxazepin-3- yl)-4H-1,2,4-triazole- 3-carboxamide

¹H NMR (DMSO-d₆) δ: 14.40 (br. s., 1H), 10.00 (s, 1H), 8.34 (br. s.,1H), 7.13- 7.33 (m, 3H), 6.99 (d, J = 10.8 Hz, 1H), 6.89 (s, 1H), 4.85(dt, J = 11.3, 7.5 Hz, 1H), 4.55-4.69 (m, 1H), 4.45 (dd, J = 10.0, 7.3Hz, 1H), 4.18 (br. s., 2H), 2.30 (s, 3H) 432 F 277 (S)-5-benzyl-N-(9-fluoro-8-methyl-2- oxo-2,3,4,5- tetrahydro-1H- benzo[b]azepin-3-yl)-4H-1,2,4-triazole-3- carboxamide

¹H NMR (DMSO-d₆) δ: 9.95 (s, 1H), 6.96-7.41 (m, 8H), 4.26-4.50 (m, 1H),4.10 (s, 2H), 2.67-2.98 (m, 3H), 2.15-2.35 (m, 4H) 394 H 278 (S)-5-(cyclopentylmethyl)- N-(5-methyl-7-(5- methyl-1,2,4- oxadiazol-3-yl)-4-oxo-2,3,4,5- tetrahydrobenzo [b][1,4]oxazepin-3- yl)-4H-1,2,4-triazole-3- carboxamide

¹H NMR (DMSO-d₆) δ: 14.20 (br. s., 1H), 8.42 (br. s., 1H), 8.02 (d, J =2.0 Hz, 1H), 7.91 (dd, J = 8.3, 2.0 Hz, 1H), 7.43 (d, J = 8.3 Hz, 1H),4.91 (dt, J = 11.6, 7.6 Hz, 1H), 4.67 (t, J = 10.7 Hz, 1H), 4.51 (dd, J= 9.9, 7.6 Hz, 1H), 3.38 (s, 3H), 2.72 (d, J = 7.6 Hz, 2H), 2.69 (s,3H), 2.25 (dt, J = 15.0, 7.6 Hz, 1H), 1.47- 1.75 (m, 6H), 1.14-1.29 (m,2H) 452 H 279 (S)-N-(5-methyl-7- (5-methyl-1,2,4- oxadiazol-3-yl)-4-oxo-2,3,4,5- tetrahydrobenzo [b][1,4]oxazepin-3- yl)-4-phenoxypicolinamide

¹H NMR (DMSO-d₆) δ: 8.67 (m, 1H), 8.45 (m, 1H), 7.29-7.07 (m, 10H), 5.04(m, 1H), 4.29-4.49 (m, 2H), 2.62-2.93 (m, 3H), 2.25 (s, 3H) 472 H 280(S)-5-benzyl-N-(8- methoxy-5-methyl- 7-(5-methyl-1,3,4-oxadiazol-2-yl)-4- oxo-2,3,4,5- tetrahydrobenzo [b][1,4]oxazepin-3-yl)-4H-1,2,4- triazole-3- carboxamide

¹H NMR (DMSO-d₆) δ: 7.88 (s, 1H), 7.12-7.43 (m, 6H), 4.91 (s, 1H), 4.61-4.73 (m, 1H), 4.46-4.57 (m, 1H), 4.13 (s, 2H), 3.92 (s, 3H), 3.31 (s,3H), 2.58 (s, 3H) 490 A 281 (S)-5-benzyl-N-(5- methyl-7-(3-methyl-1,2,4- oxadiazol-5-yl)-4- oxo-2,3,4,5- tetrahydrobenzo[b][1,4]oxazepin-3- yl)-4H-1,2,4- triazole-3- carboxamide

¹H NMR (DMSO-d₆) δ: 8.53 (d, J = 7.3 Hz, 1H), 8.16 (d, J = 2.0 Hz, 1H),8.00 (dd, J = 8.3, 2.0 Hz, 1H), 7.47 (d, J = 8.5 Hz, 1H), 7.21-7.36 (m,6H), 4.91 (dt, J = 11.6, 7.7 Hz, 1H), 4.68-4.75 (m, 1H), 4.51 (dd, J =9.8, 7.3 Hz, 1H), 4.12 (s, 2H), 3.39 (s, 3H), 2.44 (s, 3H) 460 F 282((S)-5-(cyclopentyl methyl)-N-(5- methyl-7-(3- methyl-1,2,4-oxadiazol-5-yl)-4- oxo-2,3,4,5- tetrahydrobenzo [b][1,4]oxazepin-3-yl)-4H-1,2,4- triazole-3- carboxamide

¹H NMR (DMSO-d₆) δ: 8.46 (d, J = 7.8 Hz, 1H), 8.16 (d, J = 2.0 Hz, 1H),8.01 (dd, J = 8.3, 2.0 Hz, 1H), 7.48 (d, J = 8.3 Hz, 1H), 4.92 (dt, J =11.5, 7.7 Hz, 1H), 4.67-4.76 (m, 1H), 4.52 (dd, J = 9.8. 7.5 Hz, 1H),3.40 (s, 3H), 2.72 (d, J = 7.5 Hz, 2H), 2.44 (s, 3H), 2.24 (dt, J =15.2, 7.6 Hz, 1H), 1.45-1.73 (m. 6H), 1.14-1.25 (m, 2H) 452 F 283(S)-5-benzyl-N-(5- methyl-4-oxo-7- (pyridin-2-yl)- 2,3,4,5-tetrahydrobenzo [b][1,4]oxazepin-3- yl)-4H-1,2,4- triazole-3-carboxamide

¹H NMR (DMSO-d₆) δ: 14.43 (br. s., 1H), 8.67- 8.71 (m, 1H), 8.49 (br.s., 1H), 8.17 (d, J = 2.3 Hz, 1H), 8.00-8.09 (m, 2H), 7.92 (td, J = 7.7,1.8 Hz, 1H), 7.21-7.41 (m, 7H), 4.91 (dt, J = 11.6, 7.7 Hz, 1H),4.60-4.69 (m, 1H), 4.46 (dd, J = 9.9, 7.6 Hz, 1H), 4.12 (s, 2H), 3.40(s, 3H) 455 F 284 (S)-5-benzyl-N- (6,8-difluoro-7- methyl-4-oxo-2,3,4,5-tetrahydro benzo[b][1,4]oxaze- pin-3-yl)-4H-1,2,4- triazole-3-carboxamide

¹H NMR (DMSO-d₆) δ: 10.09 (br. s., 1H), 8.49 (d, J = 7.0 Hz, 1H),7.19-7.38 (m, 5H), 7.02 (dd, J = 9.8, 1.5 Hz, 1H), 4.87 (dt, J = 11.3,7.5 Hz, 1H), 4.64 (t, J = 10.7 Hz, 1H), 4.48 (dd, J = 10.0, 7.3 Hz, 1H),4.12 (s, 2H), 2.15 (s, 3H) 414 F 285 (S)-N-(7-chloro-9- fluoro-2-oxo-2,3,4,5-tetrahydro- 1H-benzo[b] azepin-3-yl)-5- (cyclopentylmethyl)-4H-1,2,4- triazole-3- carboxamide

¹H NMR (DMSO-d₆) δ: 14.14 (s, 1H), 10.08 (s, 1H), 8.22 (d, J = 7.5 Hz,1H), 7.43-7.54 (m, 1H), 7.35 (s, 1H), 4.36 (dt, J = 11.3, 7.9 Hz, 1H),2.62- 2.88 (m, 4H), 2.34-2.48 (m, 1H), 2.19-2.32 (m, 2H), 1.44-1.78 (m,6H), 1.10-1.29 (m, 2H) 406/408 F

Example 286

Using the procedure described in Example 12,(S)-3-amino-5-methyl-2,3-dihydrobenzo[b][1,4]oxazepin-4(5H)-onehydrochloride (220 mg, 0.96 mmol) was reacted with5-(1-phenylethyl)-4H-1,2,4-triazole-3-carboxylic acid hydrochloride (256mg, 1.0 mmol) to yieldN—((S)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-5-(1-phenylethyl)-4H-1,2,4-triazole-3-carboxamide(330 mg, 89% yield) as a mixture of 2 diastereoisomers. Separation ofthe 2 diastereoisomers was achieved using a Gilson LC eluting with 20:80EtOAc/Hexane with 0.1% DEA. The 2 diastereoisomers were each isolatedwith a diastereomeric excess >99% and a yield of 138 mg of each.

N—((S)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-5-((S)-1-phenylethyl)-4H-1,2,4-triazole-3-carboxamide:¹H NMR (DMSO-d₆) δ: 8.46 (br. s., 1H), 7.51 (dd, J=7.7, 1.6 Hz, 1H),7.08-7.45 (m, 8H), 4.84 (dd, J=11.2, 8.0 Hz, 1H), 4.52-4.72 (m, 1H),4.25-4.49 (m, 2H), 3.32 (s, 3H), 1.63 (d, J=7.3 Hz, 3H). MS (m/z) 392(M+H⁺).

N—((S)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-5-((R)-1-phenylethyl)-4H-1,2,4-triazole-3-carboxamide:¹H NMR (DMSO-d₆) δ: 8.45 (br. s., 1H), 7.51 (dd, J=7.7, 1.9 Hz, 1H),7.12-7.42 (m, 9H), 4.76-4.94 (m, 1H), 4.53-4.70 (m, 1H), 4.28-4.49 (m,2H), 3.26-3.42 (m, 3H), 1.63 (d, J=7.3 Hz, 3H). MS (m/z) 392 (M+H⁺).

Pharmaceutical Compositions Example A

Tablets are prepared using conventional methods and are formulated asfollows:

Ingredient Amount per tablet Compound  5 mg Microcrystalline cellulose100 mg Lactose 100 mg Sodium starch glycollate  30 mg Magnesium stearate 2 mg Total 237 mg

Example B

Capsules are prepared using conventional methods and are formulated asfollows:

Ingredient Amount per tablet Compound  15 mg Dried starch 178 mgMagnesium stearate  2 mg Total 195 mg

Biological Assays:

Biological In Vitro Assay

A fluorescent polarization based binding assay was developed toquantitate interaction of novel test compounds at the ATP binding pocketof RIP1, by competition with a fluorescently labeled ATP competitiveligand. GST-RipK1(1-375) was purified from a Baculovirus expressionsystem and was used at a final assay concentration of 10 nM. Afluorescent labeled ligand(14-(2-{[3-({2-{[4-(cyanomethyl)phenyl]amino}-6-[(5-cyclopropyl-1H-pyrazol-3-yl)amino]-4-pyrimidinyl}amino)propyl]amino}-2-oxoethyl)-16,16,18,18-tetramethyl-6,7,7a,8a,9,10,16,18-octahydrobenzo[2″,3″]indolizino[8″,7″:5′,6′]pyrano[3′,2′:3,4]pyrido[1,2-a]indol-5-ium-2-sulfonate (prepared as described below)was used at a final assay concentration of 5 nM. Both the enzyme andligand were prepared in solutions in 50 mM HEPES pH7.5, 10 mM NaCl, 50mM MgCl2, 0.5 mM DTT, and 0.02% CHAPS. Test compounds were prepared inneat DMSO and 100 nL was dispensed to individual wells of a multiwellplate. Next, 5 ul GST-RipK1(1-375) was added to the test compounds attwice the final assay concentration, and incubated at room temperaturefor 10 minutes. Following the incubation, 5 ul of the fluorescentlabeled ligand solution, was added to each reaction, at twice the finalassay concentration, and incubated at room temperature for at least 15minutes. Finally, samples were read on an instrument capable ofmeasuring fluorescent polarization. Test compound inhibition wasexpressed as percent (%) inhibition of internal assay controls. Forconcentration response experiments, normalized data were fit and pIC₅₀sdetermined using conventional techniques. The pIC₅₀s are averaged todetermine a mean value, for a minimum of 2 experiments.

As determined using the above method, the compounds of Examples 1-286exhibited a pIC₅₀ between approximately 5.0 and 9.0. For instance, thecompounds of Examples 12, 91, 102, 161, 163 and 169 inhibited RIP1kinase in the above method with a mean pIC₅₀ of approximately 7.6, 7.6,7.8, 7.9, 7.9 and 7.2 respectively. Continued testing resulted in aslight change in the reported average pIC₅₀ for these compounds (Example161 (7.7) and Example 169 (7.3)).

Preparation of(14-(2-{[3-({2-{[4-(cyanomethyl)phenyl]amino}-6-[(5-cyclopropyl-1H-pyrazol-3-yl)amino]-4-pyrimidinyl}amino)propyl]amino}-2-oxoethyl)-16,16,18,18-tetramethyl-6,7,7a,8a,9,10,16,18-octahydrobenzo[2″,3″]indolizino[8″,7″:5′,6′]pyrano[3′,2′:3,4]pyrido[1,2-a]indol-5-ium-2-sulfonate

A solution of 2,4,6-trichloropyrimidine (Alfa, 12.25 g, 66.8 mmol),3-amino-5-cyclopropyl-1H-pyrazole (Fluorochem 8.23 g, 66.8 mmol) andtriethylamine (11.2 mL, 80.4 mmol) in ethanol (100 mL) was stirred atroom temperature for 16 hours under Ar (balloon). The solvent wasremoved in vacuo and the crude material was dissolved in ethyl acetate.The solution was washed with water and dried (Na₂SO₄), filtered andevaporated to give a beige solid. Pure product was obtained as a whitecrystalline solid after recrystallisation from acetonitrile. It waspossible to obtain a second crop. From two runs performed under the sameconditions, 29.0 g (88%) of2,6-dichloro-N-(5-cyclopropyl-1H-pyrazol-3-yl)pyrimidin-4-amine. Theproduct contained ˜10% acetonitrile but was carried through to the nextstep regardless.

A suspension of(5-cyclopropyl-1H-pyrazol-3-yl)-(2,6-dichloro-pyrimidin-4-yl)-amine(25.8 g, 0.1 mol) and 4-aminophenylacetonitrile (Alfa, 13.91 g, 0.11mol) in diisopropylethylamine (Alfa, 342 mL) was stirred at 110° C. for16 hours under Ar (balloon). The resultant gummy suspension wasdissolved in DCM, washed with water and dried (Na₂SO₄), filtered andconcentrated. When the DCM was reduced to a small volume the materialwas left to stand and the product dropped out of solution. Afterfiltration and washing with DCM, formation of2-(4-((4-chloro-6-((5-cyclopropyl-1H-pyrazol-3-yl)amino)pyrimidin-2-yl)amino)phenyl)acetonitrilewas obtained as a beige powder (10.6 g, 30.3%).

A mixture of{4-[4-chloro-6-(5-cyclopropyl-1H-pyrazol-3-ylamino)-pyrimidin-2-ylamino]-phenyl}-acetonitrile(1.54 g, 4.2 mmol) and tert-butyl N-(2-aminopropyl)carbamate (Aldrich,2.20 g, 12.6 mmol, 3.0 eq) were heated at 115° C. for 16 hours under Ar(balloon). The resultant glassy solid was purified by columnchromatography (at least 25 cm depth of silica, eluent=DCM→5% MeOH inDCM). Recovered starting material is the first yellow band to elute fromthe column (eluent ˜2% MeOH in DCM) and the product elutes when thesecond yellow band has moved through the column (eluent 4% MeOH in DCM).A purple band elutes once almost all the product has eluted. A goodeluent for TLC analysis of the fractions is 1:1 EtOAc/Pet. Ether. Theinitial fractions of the product are contaminated with a trace of higherRf material whereas the final fractions of product contain traces of alower Rf material. Therefore only the middle product fractions werecombined. tert-Butyl(3-((2-((4-(cyanomethyl)phenyl)amino)-6-((5-cyclopropyl-1H-pyrazol-3-yl)amino)pyrimidin-4-yl)amino)propyl)carbamatewas obtained as a yellow foam (0.7 g, 33.0%).

tert-Butyl(3-((2-((4-(cyanomethyl)phenyl)amino)-6-((5-cyclopropyl-1H-pyrazol-3-yl)amino)pyrimidin-4-yl)amino)propyl)carbamate(20 mg, 0.040 mmol) was dissolved in an ice-cold solution of water (0.1mL) in trifluoroacetic acid (TFA) (1.9 mL). The reaction mixture wasallowed to warm to room temperature and left for a total of 2 hours.Excess acid was removed under reduced pressure and the oily residuetriturated with several portions of dry ether. The residual solid wasdried under reduced pressure. MS (m/z) 403 (M+H⁺). Analytical C18 HPLCshowed only one major component. Yield of2-(4-((4-((3-aminopropyl)amino)-6-((5-cyclopropyl-1H-pyrazol-3-yl)amino)pyrimidin-2-yl)amino)phenyl)acetonitrileestimated at approximately 98%.

2-(4-((4-((3-Aminopropyl)amino)-6-((5-cyclopropyl-1H-pyrazol-3-yl)amino)pyrimidin-2-yl)amino)phenyl)acetonitriletrifluoroacetic acid salt (3.2 mg, 6.18 mol) and14-{2-[(2,5-dioxo-1-pyrrolidinyl)oxy]-2-oxoethyl}-16,16,18,18-tetramethyl-6,7,7a,8a,9,10,16,18-octahydrobenzo[2″,3″]indolizino[8″,7″:5′,6′]pyrano[3′,2′:3,4]pyrido[1,2-a]indol-5-ium-2-sulfonatetrifluoroacetic acid salt (2.6 mg, 3.37 μmol) were placed in a 2 mlEppendorf tube and DMF (200 μl) added. The mixture was stirred till allsolid had dissolved and then the mixture was basified by the addition ofDIPEA (2 μl, 0.011 mmol). The reaction was stirred overnight at roomtemperature. The reaction mixture was evaporated to dryness andredissolved in DMSO/MeOH (<1 ml), filtered (0.2 μm) and applied to aPhenomenex Jupiter C18 preparative column and eluted with the followinggradient (A=0.1% trifluoroacetic acid in water, B=0.1% TFA/90%acetonitrile/10% water): Flow rate=10 ml/min., AU=20/10 (214 nm). Thetarget component was eluted in two fractions. Both fractions werecombined and evaporated to dryness to yield 1.4 mg of14-(2-{[3-({2-{[4-(cyanomethyl)phenyl]amino}-6-[(5-cyclopropyl-1H-pyrazol-3-yl)amino]-4-pyrimidinyl}amino)propyl]amino}-2-oxoethyl)-16,16,18,18-tetramethyl-6,7,7a,8a,9,10,16,18-octahydrobenzo[2″,3″]indolizino[8″,7″:5′,6′]pyrano[3′,2′:3,4]pyrido[1,2-a]indol-5-ium-2-sulfonate.

GST-RipK1 Preparation: His.GST.TEV.RIPK1 1-375

The RIPK1 gene [receptor (TNFRSF)-interacting serine-threonine kinase 1]was cloned from human adrenal gland cDNA. Primers were designed from thereference sequence NM_003804.3 with an added CACC Kozak directional tagfor cloning into pENTR/TEV/D-TOPO. Gateway® LR cloning was used tosite-specifically recombine RIPK1 downstream to an N-terminal HisGSTcontained within the destination vector pDEST8-His.GST according to theprotocol described by Invitrogen. A stop codon was inserted after aminoacid 375 using Quikchange Stratagene mutagenesis kit according tomanufacturer's protocol and resulted in pDEST8.His.GST.TEV.human RIPK11-375. His.GST.Tev.human RIPK1 1-375 baculovirus was generated using thebac to bac system (Invitrogen) according to manufacturer'sspecifications. Transfection of Spodoptera frugiperda(Sf9) insect cellswas performed using Fugene 6 (Roche), according to the manufacturer'sprotocol. His.GST.TEV.human RIPK1 1-375 baculovirus infected insectcells (BIICs) were prepared during the baculovirus generation accordingto David Wasilko and S Edward Lee, TIPS: Titerless Infected CellsPreservation and Scale up, BioProcessing Journal Fall 2006 p 29-32. 20 LSf9 cells were grown in serum free Hyclone, SFX media (HyCloneLaboratories, 925 West 1800 South Logan, Utah 84321) at 27° C. in wavebags seeded at a density of 8×10{circumflex over ( )}6 cell/ml with arock rate of 25 rpm, airflow of 0.18 to 0.22. in wave reactor (WAVEBioreactor, System 20/50EH). Cells were grown ON at 27 C.His.GST.TEV.human RIPK1 1-375 baculovirus infected insect cells (BIICs)were used to infect Sf9s at a cell density of 1.7 to 2.4×10{circumflexover ( )}6. 2 ml of BIIC (1×10{circumflex over ( )}7 cells/mL) wereadded to 20 L cells. Rock rate is increased to 25 rom at infection.Harvest 72 hrs post infection using the Viafuge. Weigh pellets, sealwave bags and freeze at -80.

A 50 g cell pellet was re-suspended in 250 ml lysis buffer (50 mM TrispH 7.5, 250 mM NaCl, 1 mM DTT and Complete Protease Inhibitor tablets(1/50 ml, from Roche Diagnostics). The cells were lysed by sonication onice, 3×30″ at power level 4 using the large probe on a BransonSonicator. The suspension was then clarified by centrifugation at 15,000g for 30 minutes, at 4° C. The lysate was decanted from the insolublepellet and batch bound to 10 ml of Glutathione Agarose (Pierce) for 2 hat 4 C with gentle end over end rotation. The beads were then packedinto a column and washed to baseline with lysis buffer (no proteaseinhibitors) and then eluted with 20 mM reduced glutathione in 50 mMTris, pH8.

Fractions identified by SDS-PAGE as containing protein of interest werepooled (10 ml total volume), concentrated to about 5 ml and loaded ontoa 300 ml SDX200 SEC column (GE Healthcare) which had been equilibratedin 50 mM Tris, pH7.5, 150 mM NaCl, 1 mM DTT and 10% Glycerol. The Riplprotein eluted as a dimer off the SEC column.

The protein concentration was determined by Bradford assay using BSA asa standard. The yield was 12.5 mg at 0.63 mg/ml. The purity was >95% asdetermined by scanning a Coomassie stained SDS-PAGE gel.

LCMS analysis showed that the major species had lost the N-terminalmethionine, was acetylated and had one phosphorylated site. The proteinwas aliquoted and frozen at -80° C. for use as needed.

Biological In Vivo Assay

The efficacy of RIP1 inhibitors can be tested in mice in vivo using aTNF-driven systemic inflammatory response syndrome model (Duprez, L., etal. 2011. Immunity 35(6):908-918). The model can be run in a longmodality (using TNF alone i.v.) which results in the termination of thestudy in ˜7 hrs (under IACUC guidelines for temperature loss) or a shortmodality (using TNF plus the caspase inhibitor zVAD i.v.) which needs tobe terminated at ˜3 hrs (under IACUC guidelines for temperature loss).TNF (or TNF/zVAD) induced manifestations include temperature loss, theproduction of numerous cytokines (including IL-6, IL-1b, MIP1β and MIP2)in the periphery, liver and intestinal inflammation and an increase ofmarkers of cellular (LDH and CK) and liver damage (AST and ALT) in theserum. Inhibition of these TNF (or TNF/zVAD) induced manifestations canbe shown by orally or IP pre-dosing with selected compounds of thisinvention.

Each test compound is run through the TNF/zVAD and TNF (alone) versionsof the model. For example, mice (7 mice per group) were orally pre-dosedwith vehicle or test compound at 50 mg/kg 15 minutes before i.v.administration of mouse TNF (30 g/mouse) and zVAD (0.4 mg/mouse)simultaneously. Temperature loss in the mice was measured by rectalprobe. The study was terminated when the control group lost 7 degrees,per our IACUC protocol. Representative data expressed over time or atthe 2.5 hour time point is provided in FIGS. 1A, 1B, 4A and 4B,respectively. All data are shown as means±standard error of the mean.Data for compounds tested in this model are provided in Table 2.

TABLE 2 Example No. Dose (mg/kg) % Inhibition 12 30 93 20 30 52 45 10 9164 30 62 125 30 25 108 30 56 161 50 85 163 10 73 176 30 34 190 30 85 9730 70 235 30 58 236 30 23

In addition to the TNF/zVAD model, each compound is also tested in a TNFalone model. For the TNF (alone) version of the model, mice (7 mice pergroup) were orally pre-dosed with vehicle or test compound at 50 mg/kg15 minutes before i.v. administration of mouse TNF (30 g/mouse). Anexample of the TNF (alone) model over time and at the 6 hour time pointcan be seen in FIGS. 2A, 2B, 5A and 5B, respectively. All data are shownas means±standard error of the mean. Data for compounds tested in thismodel are provided in Table 3.

TABLE 3 Example No. Dose (mg/kg) % Inhibition 12 50 87 20 50 51 161 5082 190 50 56 235 50 73

Biological In Vitro Cell Assay

The efficacy of RIP1 inhibitors can be tested in mice in vitro using ahuman monocytic leukemia U937 or mouse L929 fibrosarcoma cells in anecroptosis assay (He, S. et al. 2009. Cell 137(6):1100-1111). Cellswere maintained in RPMI supplemented with 10% fetal bovine serum 100U/ml penicillin, 100 ug/ml streptomycin. For the assay, cells weresuspended at 5e5 cells/ml in phenol red free RPMI supplemented with 1%fetal bovine serum, 100 U/ml penicillin, 100 ug/ml streptomycin.Thirty-five (35) ul of the cell suspension was aliquotted into a white,half area assay plate. Five (5) ul each of QVD (final concentration 50uM) or compound was added to the cells and incubated at 37° C. for 30min to 1 h. Following the incubation, 5 ul TNFα (final concentration 100ng/ml) was added to the cells and the samples were incubated overnight.The next day, cellular levels of ATP was determined using the CellTiter-Glo Luminescent Cell Viability kit (available from PromegaCorporation, Madison, Wis., USA). For example, L929 (FIG. 3A) or U937(FIG. 3B) cells were treated with vehicle or 10 μM of Example 77. Forexample, L929 (FIG. 6A) or U937 (FIG. 6B) cells were treated withvehicle or indicated concentrations of the compound of Example 161.Viability was measured by quantitating cellular levels of ATP using theCell Titer-Glo kit. All data are shown as means±standard deviation ofthe mean.

What is claimed is:
 1. A compound according to Formula (I):

wherein: X is NH; Y is CH₂ or CH₂CH₂; Z¹ is N, CH or CR¹; Z² is CH orCR²; Z³ is N, CH or CR³; Z⁴ is CH or CR⁴; R¹ is fluoro or methyl; one ofR² and R³ is halogen, cyano, (C₁-C₆)alkyl, halo(C₁-C₄)alkyl,(C₁-C₆)alkoxy, halo(C₁-C₄)alkoxy, hydroxyl, B(OH)₂, —COOH,halo(C₁-C₄)alkylC(OH)₂—, (C₁-C₄)alkoxy(C₁-C₄)alkoxy, (C₁-C₄)alkylSO₂-,(C₁-C₄)alkylSO₂NHC(O)—, (C₁-C₄)alkylC(O)NH—,((C₁-C₄)alkyl)((C₁-C₄)alkyl)NC(O)—, (C₁-C₄)alkylOC(O)—,(C₁-C₄)alkylC(O)N(C₁-C₄)alkyl)-, (C₁-C₄)alkylNHC(O)—,(C₁-C₄)alkoxy(C₂-C₄)alkylNHC(O)—, (C₁-C₄)alkoxy(C₂-C₄)alkylC(O)NH—,(C₁-C₄)alkoxy(C₂-C₄)alkylNHC(O)NH—, (C₁-C₄)alkylSO₂(C₂-C₄)alkylNHC(O)—,(C₁-C₄)alkylNHC(O)NH—, (C₁-C₄)alkylOC(O)NH—,hydroxy(C₁-C₄)alkylOC(O)NH—, 5-6 membered heterocycloalkyl-C(O)—, 5-6membered heterocycloalkyl-(C₁-C₄)alkyl-NHC(O)—, 5-6 memberedheterocycloalkyl-(C₁-C₄)alkoxy-, 3-6 membered cycloalkyl, 5-6 memberedheteroaryl, or 5-6 membered heteroaryl-C(O)NH, wherein said 3-6 memberedcycloalkyl, 5-6 membered heterocycloalkyl and 5-6 membered heteroarylare optionally substituted by 1 or 2 substituents each independentlyselected from the group consisting of (C₁-C₄)alkyl and —(C₁-C₄)alkyl-CN;and the other of R² and R³ is halogen, cyano or (C₁-C₆)alkyl; R⁴ isfluoro, chloro, methyl or trifluoromethyl; R⁵ is H or methyl; A isphenyl, 5-6 membered heteroaryl, or 5-6 membered heterocycloalkyl,wherein the carbonyl moiety and L are substituted 1,3 on ring A; m is 0or m is 1 and R^(A) is (C₁-C₄)alkyl; and L is O, S, NH, N(CH₃), CH₂,CH₂CH₂, CH(CH₃), CHF, CF₂, CH₂O, CH₂N(CH₃), CH₂NH, or CH(OH); B is anoptionally substituted (C₃-C₆)cycloalkyl, phenyl, 5-6 memberedheteroaryl, or 5-6 membered heterocycloalkyl; wherein said(C₃-C₆)cycloalkyl, phenyl, 5-6 membered heteroaryl, or 5-6 memberedheterocycloalkyl is unsubstituted or is substituted by one or twosubstituents each independently selected from halogen, (C₁-C₄)alkyl,halo(C₁-C₄)alkyl, (C₁-C₄)alkoxy, halo(C₁-C₄)alkoxy, nitro, and(C₁-C₄)alkylC(O)—; or the moiety -L-B is (C₃-C₆)alkyl, (C₃-C₆)alkoxy,halo(C₃-C₆)alkoxy, (C₃-C₆)alkenyl, or (C₃-C₆)alkenyloxy; or apharmaceutically acceptable salt thereof.
 2. The compound according toclaim 1, or pharmaceutically acceptable salt thereof, wherein: X is NH;Y is CH₂ or CH₂CH₂; Z¹ is N, CH or CR¹; Z² is CH or CR²; Z³ is N, CH orCR³; Z⁴ is CH or CR⁴; R¹ is fluoro or methyl; one of R² and R³ ishalogen, cyano, (C₁-C₆)alkyl, halo(C₁-C₄)alkyl, (C₁-C₆)alkoxy,halo(C₁-C₄)alkoxy, hydroxyl, B(OH)₂, —COOH, halo(C₁-C₄)alkylC(OH)₂—,(C₁-C₄)alkoxy(C₁-C₄)alkoxy, (C₁-C₄)alkylSO₂-, (C₁-C₄)alkylSO₂NHC(O)—,(C₁-C₄)alkylC(O)NH—, ((C₁-C₄)alkyl)((C₁-C₄)alkyl)NC(O)—,(C₁-C₄)alkylOC(O)—, (C₁-C₄)alkylC(O)N(C₁-C₄)alkyl)-,(C₁-C₄)alkylNHC(O)—, (C₁-C₄)alkoxy(C₂-C₄)alkylNHC(O)—,(C₁-C₄)alkoxy(C₂-C₄)alkylC(O)NH—, (C₁-C₄)alkoxy(C₂-C₄)alkylNHC(O)NH—,(C₁-C₄)alkylSO₂(C₂-C₄)alkylNHC(O)—, (C₁-C₄)alkylNHC(O)NH—,(C₁-C₄)alkylOC(O)NH—, hydroxy(C₁-C₄)alkylOC(O)NH—, 5-6 memberedheterocycloalkyl-C(O)—, 5-6 memberedheterocycloalkyl-(C₁-C₄)alkyl-NHC(O)—, 5-6 memberedheterocycloalkyl-(C₁-C₄)alkoxy-, 3-6 membered cycloalkyl, 5-6 memberedheteroaryl, or 5-6 membered heteroaryl-C(O)NH, wherein said 3-6 memberedcycloalkyl, 5-6 membered heterocycloalkyl and 5-6 membered heteroarylare optionally substituted by 1 or 2 substituents each independentlyselected from the group consisting of (C₁-C₄)alkyl and —(C₁-C₄)alkyl-CN;and the other of R² and R³ is halogen or (C₁-C₆)alkyl; R⁴ is fluoro,chloro, or methyl; R⁵ is H or methyl; A is phenyl, 5-6 memberedheteroaryl, or 5-6 membered heterocycloalkyl, wherein the carbonylmoiety and L are substituted 1,3 on ring A; m is 0 or m is 1 and R^(A)is (C₁-C₄)alkyl; and L is O, S, NH, N(CH₃), CH₂, CH₂CH₂, CH(CH₃), CHF,CF₂, CH₂O, CH₂N(CH₃), CH₂NH, or CH(OH); B is an optionally substituted(C₃-C₆)cycloalkyl, phenyl, 5-6 membered heteroaryl, or 5-6 memberedheterocycloalkyl; wherein said (C₃-C₆)cycloalkyl, phenyl, 5-6 memberedheteroaryl, or 5-6 membered heterocycloalkyl is unsubstituted or issubstituted by one or two substituents each independently selected fromhalogen, (C₁-C₄)alkyl, halo(C₁-C₄)alkyl, (C₁-C₄)alkoxy,halo(C₁-C₄)alkoxy, nitro, and (C₁-C₄)alkylC(O)—; or the moiety -L-B is(C₃-C₆)alkyl, (C₃-C₆)alkoxy, halo(C₃-C₆)alkoxy, (C₃-C₆)alkenyl, or(C₃-C₆)alkenyloxy.
 3. The compound according to claim 1, orpharmaceutically acceptable salt thereof, wherein: X is NH; Y is CH₂ orCH₂CH₂; Z¹ is N, CH or CR¹; Z² is CH or CR²; Z³ is N, CH or CR³; Z⁴ isCH or CR⁴; R¹ is fluoro or methyl; one of R² and R³ is halogen, cyano,(C₁-C₆)alkyl, halo(C₁-C₄)alkyl, (C₁-C₆)alkoxy, hydroxyl, B(OH)₂, —COOH,halo(C₁-C₄)alkylC(OH)₂—, (C₁-C₄)alkoxy(C₁-C₄)alkoxy, (C₁-C₄)alkylSO₂-,(C₁-C₄)alkylSO₂NHC(O)—, (C₁-C₄)alkylC(O)NH—,((C₁-C₄)alkyl)((C₁-C₄)alkyl)NC(O)—, (C₁-C₄)alkylOC(O)—,(C₁-C₄)alkylC(O)N(C₁-C₄)alkyl)-, (C₁-C₄)alkylNHC(O)—,(C₁-C₄)alkoxy(C₂-C₄)alkylNHC(O)—, (C₁-C₄)alkoxy(C₂-C₄)alkylC(O)NH—,(C₁-C₄)alkoxy(C₂-C₄)alkylNHC(O)NH—, (C₁-C₄)alkylSO₂(C₂-C₄)alkylNHC(O)—,(C₁-C₄)alkylNHC(O)NH—, (C₁-C₄)alkylOC(O)NH—,hydroxy(C₁-C₄)alkylOC(O)NH—, 5-6 membered heterocycloalkyl-C(O)—, 5-6membered heterocycloalkyl-(C₁-C₄)alkyl-NHC(O)—, 5-6 memberedheterocycloalkyl-(C₁-C₄)alkoxy-, 3-6 membered cycloalkyl, 5-6 memberedheteroaryl, or 5-6 membered heteroaryl-C(O)NH, wherein said 5-6 memberedheterocycloalkyl and 5-6 membered heteroaryl are optionally substitutedby 1 or 2 substituents each independently selected from the groupconsisting of (C₁-C₄)alkyl and —(C₁-C₄)alkyl-CN; and the other of R² andR³ is halogen or (C₁-C₆)alkyl; R⁴ is fluoro, chloro, or methyl; R⁵ is Hor methyl; A is phenyl, 5-6 membered heteroaryl, or 5-6 memberedheterocycloalkyl, wherein the carbonyl moiety and L are substituted 1,3on ring A; m is 0 or m is 1 and R^(A) is (C₁-C₄)alkyl; and L is O, S,NH, N(CH₃), CH₂, CH₂CH₂, CH(CH₃), CHF, CF₂, CH₂O, CH₂N(CH₃), CH₂NH, orCH(OH); B is an optionally substituted (C₃-C₆)cycloalkyl, phenyl, 5-6membered heteroaryl, or 5-6 membered heterocycloalkyl; wherein said(C₃-C₆)cycloalkyl, phenyl, 5-6 membered heteroaryl, or 5-6 memberedheterocycloalkyl is unsubstituted or is substituted by one or twosubstituents each independently selected from halogen, (C₁-C₄)alkyl,halo(C₁-C₄)alkyl, (C₁-C₄)alkoxy, halo(C₁-C₄)alkoxy, nitro, and(C₁-C₄)alkylC(O)—; or the moiety -L-B is (C₃-C₆)alkyl, (C₃-C₆)alkoxy,halo(C₃-C₆)alkoxy, (C₃-C₆)alkenyl, or (C₃-C₆)alkenyloxy.
 4. The compoundaccording to claim 1, or pharmaceutically acceptable salt thereof,wherein: X is NH; Y is CH₂ or CH₂CH₂; Z¹, Z², Z³, and Z⁴ are each CH; orZ¹ is CR¹ and Z², Z³ and Z⁴ are each CH; or Z¹, Z², and Z⁴ are each CHand Z³ is CR³; or Z¹, Z³, and Z⁴ are each CH and Z² is CR²; or Z¹, Z²,and Z³ are each CH and Z⁴ is CR⁴; or Z¹ and Z³ are CH, Z² is CR², and Z⁴is CR⁴; or Z¹ and Z³ are both N, Z² is CH and Z⁴ is CH or CR⁴; or Z¹ isN, Z² is CR² and Z³ and Z⁴ are CH; or Z³ is N, and Z², Z³ and Z⁴ are CH;R¹ is methyl, R² is chloro, bromo, —CN, —CH₃, OH, B(OH)₂, CF₃C(OH)₂,CH₃OCH₂CH₂O—, 5H-tetrazol-5-yl, pyrazol-3-yl, or5-methyl-1,3,4-oxadiazol-2-yl; R³ is fluoro, chloro, bromo, —OCH₃,B(OH)₂, —COOH, CH₃SO₂—, CH₃SO₂NHC(O)—, CH₃C(O)NH—, (CH₃)₂NC(O)—,CH₃OC(O)—, (CH₃)C(O)N(CH₃)—, HOCH₂CH₂C(O)NH—, CH₃OCH₂CH₂NHC(O)NH—,CH₃SO₂CH₂CH₂NHC(O)—, CH₃CH₂NHC(O)NH—, CH₃OC(O)NH—, morpholin-4-yl-CO—,pyrrolidin-1-yl-CH₂CH₂NHC(O)—, tetrahydrofuran-2-yl-CH₂O—,pyrrolidin-1-yl-CH₂CH₂O—, tetrazol-5-yl, 1-(2-cyanoethyl)-tetrazol-5-yl,pyrazol-1-yl, pyrazol-3-yl, 1-methyl-pyrazol-3-yl,1-methyl-pyrrol-4-yl-C(O)NH—, or 5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl;R⁴ is fluoro or methyl; A is furyl, thienyl, oxazolyl, isoxazolyl,thiazolyl, 1, 2, 4-oxadiazolyl, 1, 3, 4-oxadiazolyl, pyrrolyl,pyrazolyl, imidazolyl, 1, 2, 3-triazolyl, 1, 2, 4-triazolyl, tetrazolyl,piperidinyl, pyrrolidinyl, phenyl or pyridyl; m is 0 or m is 1 and R^(A)is methyl; L is O, S, N(CH₃), CH₂, CH₂CH₂, CH(CH₃), CF₂, CH₂O,CH₂N(CH₃), or CH(OH); and B is thien-2-yl, pyrazol-1-yl,3,5-dimethylpyrazol-1-yl, 4-methylpyrazol-1-yl,3,5-dimethylisoxazol-4-yl, tetrahydrofuran-2-yl, morpholin-4-yl,pyridin-2-yl, 2-oxo-pyridin-1-yl, 6-methylpyridin-3-yl,2-methylpyrimidin-5-yl, cyclopentyl, cyclohexyl, phenyl, 2-methylphenyl,4-methylphenyl, 2-trifluoromethylphenyl, 2-fluorophenyl, 3-fluorophenyl,4-fluorophenyl, 2-iodophenyl, 3-bromophenyl, 4-bromophenyl,4-chlorophenyl, 2,5-difluorophenyl, 2,4-difluorophenyl,3,4-difluorophenyl, 3,5-difluorophenyl, or 4-methoxyphenyl; or -L-B isOCH₂CH═CH₂, —CH₂CH₂CH₂CH₂CH₃, —OCH₂CH₂CH₂CH₃, —CH₂CH₂CH₃, or—CH₂CH(CH₃)₂.
 5. The compound according to claim 1, or pharmaceuticallyacceptable salt thereof, wherein Y is CH₂.
 6. The compound according toclaim 2, or pharmaceutically acceptable salt thereof, wherein Y is CH₂.7. The compound according to claim 3, or pharmaceutically acceptablesalt thereof, wherein Y is CH₂
 8. The compound according to claim 4, orpharmaceutically acceptable salt thereof, wherein Y is CH₂.
 9. Apharmaceutical composition comprising the compound according to claim 1,or pharmaceutically acceptable salt thereof, and one or morepharmaceutically acceptable excipients.
 10. A method of treating a RIP1kinase mediated disease or disorder comprising administering atherapeutically effective amount of the compound or pharmaceuticallyacceptable salt thereof, according to claim 1 to a human in needthereof, wherein the disease or disorder is selected from ulcerativecolitis, Crohn's disease, rheumatoid arthritis, psoriasis,spondyloarthritis, systemic onset juvenile idiopathic arthritis,psoriatic arthritis, osteoarthritis, multiple sclerosis, sepsis,ischemia reperfusion injury of solid organs, and systemic inflammatoryresponse syndrome.